106 results on '"Mark A, Ator"'
Search Results
2. Supplementary Table 1, Figures 1-2 from CEP-28122, a Highly Potent and Selective Orally Active Inhibitor of Anaplastic Lymphoma Kinase with Antitumor Activity in Experimental Models of Human Cancers
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Bruce A. Ruggeri, Giorgio Inghirami, Bruce D. Dorsey, Mark A. Ator, Cristina Abele, Rodolfo Machiorlatti, Flavio Cristofani, Lisa D. Aimone, Thelma S. Angeles, Mark S. Albom, Weihua Wan, Lihui Lu, Gregory R. Ott, Diane E. Gingrich, Matthew R. Quail, and Mangeng Cheng
- Abstract
PDF file - 300K
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- 2023
3. Supplementary Data 1 from CEP-32496: A Novel Orally Active BRAFV600E Inhibitor with Selective Cellular and In Vivo Antitumor Activity
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Mark W. Holladay, Shripad S. Bhagwat, Michael Williams, Bruce D. Dorsey, Raffaella Faraoni, Julius L. Apuy, Mark A. Ator, Darren E. Insko, Mehran Yazdanian, Dana Gitnick, Mangeng Cheng, Ronald R. Nepomuceno, Kathryn Hunter, Merryl D. Cramer, Hugh Zhao, Michael F. Gardner, Pawel Dobrzanski, Ruwanthi N. Gunawardane, Susan Jones-Bolin, Martin W. Rowbottom, Robert C. Armstrong, Bruce Ruggeri, and Joyce James
- Abstract
PDF file - 74K, CEP-32496 Supplemental Data.
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- 2023
4. Novel Macrocyclic Antagonists of the Calcitonin Gene-Related Peptide Receptor: Design, Realization, and Structural Characterization of Protein–Ligand Complexes
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Andrew D. Cansfield, Mark A. Ator, Joydeep Banerjee, Michael Bestwick, Andrea Bortolato, Giles A. Brown, Jason Brown, Kristina Butkovic, Julie E. Cansfield, John A. Christopher, Miles Congreve, Gabriella Cseke, Francesca Deflorian, Benjamin Dugan, Martina Petrovic Hunjadi, Antun Hutinec, Trinadh Kumar Inturi, Goran Landek, Jonathan Mason, Alistair O’Brien, Gregory R. Ott, Renata Rupcic, Gordon Saxty, Stacey M. Southall, Rahela Zadravec, and Stephen P. Watson
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GPCR CGRP CGRPR macrocycle macrocyclic antagonist ,Physiology ,Cognitive Neuroscience ,Calcitonin Receptor-Like Protein ,Cell Biology ,General Medicine ,Crystallography, X-Ray ,Ligands ,Biochemistry ,Receptors, Calcitonin Gene-Related Peptide ,Receptors, G-Protein-Coupled - Abstract
A series of macrocyclic calcitonin gene-related peptide (CGRP) receptor antagonists identified using structure-based design principles, exemplified by HTL0028016 (1) and HTL0028125 (2), is described. Structural characterization by X-ray crystallography of the interaction of two of the macrocycle antagonists with the CGRP receptor ectodomain is described, along with structure– activity relationships associated with point changes to the macrocyclic antagonists. The identification of non-peptidic/natural product- derived, macrocyclic ligands for a G protein coupled receptor (GPCR) is noteworthy.
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- 2022
5. Structure-Based Drug Discovery of
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Sarah J, Bucknell, Mark A, Ator, Alastair J H, Brown, Jason, Brown, Andrew D, Cansfield, Julie E, Cansfield, John A, Christopher, Miles, Congreve, Gabriella, Cseke, Francesca, Deflorian, Christopher R, Jones, Jonathan S, Mason, M Alistair, O'Brien, Gregory R, Ott, Mark, Pickworth, and Stacey M, Southall
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Binding Sites ,Indazoles ,Molecular Structure ,Migraine Disorders ,Rats ,Molecular Docking Simulation ,Macaca fascicularis ,Structure-Activity Relationship ,Dogs ,Calcitonin Gene-Related Peptide Receptor Antagonists ,Drug Design ,Animals ,Humans ,Spiro Compounds ,Receptors, Calcitonin Gene-Related Peptide - Abstract
Structure-based drug design enabled the discovery of
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- 2020
6. 3-(1′-Cyclobutylspiro[4H-1,3-benzodioxine-2,4′-piperidine]-6-yl)-5,5-dimethyl-1,4-dihydropyridazin-6-one (CEP-32215), a new wake-promoting histamine H3 antagonist/inverse agonist
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Robert L. Hudkins, Joanne R. Mathiasen, Rita Raddatz, Edward R. Bacon, Michael J. Marino, Mark A. Ator, Michael Williams, Lisa D. Aimone, and John A. Gruner
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Male ,0301 basic medicine ,medicine.medical_specialty ,Drug Inverse Agonism ,Drinking ,Drug Evaluation, Preclinical ,Administration, Oral ,Biological Availability ,Motor Activity ,Pharmacology ,Histamine agonist ,Histamine Agonists ,Rats, Sprague-Dawley ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Histamine receptor ,chemistry.chemical_compound ,Dogs ,0302 clinical medicine ,Therapeutic index ,Piperidines ,Internal medicine ,medicine ,Animals ,Humans ,Receptors, Histamine H3 ,Inverse agonist ,Spiro Compounds ,Wakefulness ,Chemistry ,Methylhistamines ,Antagonist ,Brain ,Macaca fascicularis ,030104 developmental biology ,Endocrinology ,Pyrazines ,Histamine H3 receptor ,Sleep ,030217 neurology & neurosurgery ,Histamine ,Histamine H3 Antagonists - Abstract
CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H3 receptor (H3R) with drug-like properties. High affinity in human (hH3R Ki = 2.0 ± 0.2 nM) and rat (rH3R Ki = 3.6 ± 0.7 nM) H3R radioligand binding assays was demonstrated. Potent functional antagonism (Kb = 0.3 ± 0.1 nM) and inverse agonism (EC50 = 0.6 ± 0.2 nM) were demonstrated in [(35)S]guanosine 5(')-O-(γ-thio)-triphosphate binding assays. Oral bioavailability and dose-related exposure was consistent among rat, dog, and monkey. After oral dosing, occupancy of H3R by CEP-32215 was estimated by the inhibition of ex vivo binding in rat cortical slices (ED50 = 0.1 mg/kg p.o.). Functional antagonism in brain was demonstrated by the inhibition of R-α-methylhistamine-induced drinking in the rat dipsogenia model (ED50 = 0.92 mg/kg). CEP-32215 significantly increased wake duration in the rat EEG model at 3-30 mg/kg p.o. Increased motor activity, sleep rebound or undesirable events (such as spike wave or seizure activity) was not observed following doses up to 100 mg/kg p.o., indicating an acceptable therapeutic index. CEP-32215 may have potential utility in the treatment of a variety of sleep disorders. This article is part of the Special Issue entitled 'Histamine Receptors'.
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- 2016
7. Combined inhibition of atypical PKC and histone deacetylase 1 is cooperative in basal cell carcinoma treatment
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A. Mirza, Bruce R. Ruggeri, Tyler Hollmig, Marina Sirota, Craig A. Zificsak, Jon Roffey, Nicole M. Urman, Bruce D. Dorsey, Gregory R. Ott, Sumaira Z. Aasi, Alexander S. Brown, Kavita Y. Sarin, Alexander Lee, Micah A. Fry, Bin Chen, Anthony E. Oro, Ervin H. Epstein, Atul J. Butte, Jean Y. Tang, Mark A. Ator, and Scott X. Atwood
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0301 basic medicine ,Skin Neoplasms ,Basal Cell ,Histone Deacetylase 1 ,Mice ,0302 clinical medicine ,Drug Discovery ,Medicine ,Protein Kinase C ,Cancer ,Mice, Knockout ,Histone deacetylase 5 ,Tumor ,biology ,integumentary system ,General Medicine ,Allografts ,Gene Expression Regulation, Neoplastic ,Isoenzymes ,Drug repositioning ,Drug Combinations ,Hedgehogs ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Development of treatments and therapeutic interventions ,medicine.drug ,Research Article ,Signal Transduction ,animal structures ,Knockout ,Zinc Finger Protein GLI1 ,Cell Line ,03 medical and health sciences ,Rare Diseases ,In vivo ,GLI1 ,Cell Line, Tumor ,Genetics ,Animals ,Vorinostat ,Cell Proliferation ,Neoplastic ,business.industry ,Gene Expression Profiling ,Carcinoma ,Computational Biology ,HDAC1 ,Histone Deacetylase Inhibitors ,030104 developmental biology ,Orphan Drug ,Gene Expression Regulation ,Carcinoma, Basal Cell ,Cancer research ,biology.protein ,Histone deacetylase ,business ,Smoothened ,Transcription Factors - Abstract
Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the FDA-approved histone deacetylase (HDAC) inhibitor, vorinostat, as a top therapeutic candidate. We show that vorinostat only inhibits proliferation of BCC cells in vitro and BCC allografts in vivo at high dose, limiting its usefulness as a monotherapy. We leveraged this in silico approach to identify drug combinations that increase the therapeutic window of vorinostat and identified atypical PKC Ɩ/ʎ (aPKC) as a HDAC costimulator of HH signaling. We found that aPKC promotes GLI1-HDAC1 association in vitro, linking two positive feedback loops. Combination targeting of HDAC1 and aPKC robustly inhibited GLI1, lowering drug doses needed in vitro, in vivo, and ex vivo in patient-derived BCC explants. We identified a bioavailable and selective small-molecule aPKC inhibitor, bringing the pharmacological blockade of aPKC and HDAC1 into the realm of clinical possibility. Our findings provide a compelling rationale and candidate drugs for combined targeting of HDAC1 and aPKC in HH-dependent cancers.
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- 2017
8. Piperidine-3,4-diol and piperidine-3-ol derivatives of pyrrolo[2,1-f][1,2,4]triazine as inhibitors of anaplastic lymphoma kinase
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R. Curtis Haltiwanger, Mark A. Olsen, Mark A. Ator, Emily Kordwitz, Gregory R. Ott, Jason C. Wagner, Bruce D. Dorsey, Zeqi Huang, Mangeng Cheng, Bruce Ruggeri, Eugen F. Mesaros, Weihua Wan, Lihui Lu, Amy J. Landis, Lisa D. Aimone, Mark S. Albom, and Thelma S. Angeles
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Models, Molecular ,Stereochemistry ,Clinical Biochemistry ,Diol ,Pharmaceutical Science ,Antineoplastic Agents ,Mice, SCID ,Crystallography, X-Ray ,Biochemistry ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Piperidines ,In vivo ,Cell Line, Tumor ,hemic and lymphatic diseases ,Drug Discovery ,Animals ,Humans ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,Pyrroles ,Protein Kinase Inhibitors ,Molecular Biology ,Triazine ,Triazines ,Kinase ,Organic Chemistry ,Autophosphorylation ,Receptor Protein-Tyrosine Kinases ,Biological activity ,chemistry ,Lymphoma, Large-Cell, Anaplastic ,Molecular Medicine ,Piperidine - Abstract
The diastereoselective synthesis and biological activity of piperidine-3,4-diol and piperidine-3-ol-derived pyrrolotriazine inhibitors of anaplastic lymphoma kinase (ALK) are described. Although piperidine-3,4-diol and piperidine-3-ol derivatives showed comparable in vitro ALK activity, the latter subset of inhibitors demonstrated improved physiochemical and pharmacokinetic properties. Furthermore, the stereochemistry of the C3 and C4 centers had a marked impact on the in vivo inhibition of ALK autophosphorylation. Thus, trans-4-aryl-piperidine-3-ols (22) were more potent than the cis diastereomers (20).
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- 2015
9. Time-Resolved Fluorescence Resonance Energy Transfer as a Versatile Tool in the Development of Homogeneous Cellular Kinase Assays
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Sheryl L. Meyer, Jean Husten, Thelma S. Angeles, Chrysanthe Spais, Mark A. Ator, Seetha Murthy, Jennifer L. Mason, Mark S. Albom, and Lisa Saville
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DNA, Complementary ,Drug Evaluation, Preclinical ,Protein tag ,Polymerase Chain Reaction ,Antibodies ,Receptor tyrosine kinase ,Cell Line ,Focal adhesion ,Proto-Oncogene Proteins ,Drug Discovery ,Fluorescence Resonance Energy Transfer ,Humans ,Enzyme Inhibitors ,Coloring Agents ,c-Mer Tyrosine Kinase ,biology ,Kinase ,Cellular Assay ,Phosphotransferases ,Receptor Protein-Tyrosine Kinases ,Fusion protein ,Antibodies, Anti-Idiotypic ,Förster resonance energy transfer ,Biochemistry ,Data Interpretation, Statistical ,Focal Adhesion Protein-Tyrosine Kinases ,biology.protein ,Molecular Medicine ,Fluorescein ,Tyrosine kinase - Abstract
Homogeneous cellular assays can streamline product detection in the drug discovery process. One commercially available assay employing time-resolved fluorescence resonance energy transfer (TR-FRET) that detects phosphorylated products was used to evaluate inhibitors of the receptor tyrosine kinase AXL in a cell line expressing an AXL-green fluorescent protein fusion protein. This TR-FRET assay was modified to evaluate the phosphorylation state of the AXL family member MER in a cell line expressing MER with a V5 tag by adding a fluorescein-labeled anti-V5 antibody. This homogeneous cellular assay was further modified to evaluate the nonreceptor tyrosine kinase focal adhesion kinase (FAK) in cell lines that expressed an untagged kinase by the inclusion of a commercially available anti-FAK antibody conjugated with an acceptor dye. The methods described here can be further adapted for TR-FRET detection of other cellular kinase activities.
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- 2012
10. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor
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Rina Kashi, Aric Orbach, Victor Piryatinsky, Daphna Laifenfeld, Mark A. Ator, Tal Birnberg, Doron Shinar, Tal Hingaly, Efrat Rubinstein, Emanuel Raymond, Einat Amit-Romach, Fadi Towfic, Ralph Laufer, Yael Marantz, Iris Grossman, Joel Kaye, Ignacio S. Caballero, Volker Knappertz, and Michael R. Hayden
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0301 basic medicine ,Encephalomyelitis, Autoimmune, Experimental ,T-Lymphocytes ,Gene Expression ,Quinolones ,Biology ,Myelin oligodendrocyte glycoprotein ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Immune system ,Cytochrome P-450 CYP1A1 ,medicine ,Animals ,Humans ,Neuroinflammation ,Mice, Knockout ,Multidisciplinary ,Microglia ,Gene Expression Profiling ,Multiple sclerosis ,Experimental autoimmune encephalomyelitis ,respiratory system ,medicine.disease ,Aryl hydrocarbon receptor ,030104 developmental biology ,medicine.anatomical_structure ,PNAS Plus ,Gene Expression Regulation ,Receptors, Aryl Hydrocarbon ,chemistry ,Immune System ,Immunology ,Hepatocytes ,biology.protein ,Female ,Transcriptome ,Laquinimod ,Gene Deletion - Abstract
Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington’s disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR−/− mice. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whereas deletion within the CNS partially abrogates the effect of laquinimod in EAE. These data strongly support the idea that AhR is necessary for the efficacy of laquinimod in EAE and that laquinimod may represent a first-in-class drug targeting AhR for the treatment of multiple sclerosis and other neurodegenerative diseases.
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- 2016
11. Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK)
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Nathan Anderson, Diane E. Gingrich, Arup K. Ghose, Mark S. Albom, Bruce D. Dorsey, Lisa D. Aimone, Elizabeth Bruckheimer, Jason C. Wagner, Matthew A. Curry, Lihui Lu, Jay Friedman, Mark A. Ator, Bruce Ruggeri, Eugen F. Mesaros, Mangeng Cheng, Zeqi Huang, Keith S. Learn, Matthew R. Quail, Thelma S. Angeles, Pawel Dobrzanski, Gregory R. Ott, Sandra V. Fernandez, Joseph G. Lisko, Kevin J. Wells-Knecht, and Weihua Wan
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0301 basic medicine ,Models, Molecular ,medicine.drug_class ,Administration, Oral ,Mice, Nude ,Mice, SCID ,Metastasis ,Focal adhesion ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,0302 clinical medicine ,In vivo ,hemic and lymphatic diseases ,Cell Line, Tumor ,Drug Discovery ,medicine ,Anaplastic lymphoma kinase ,Animals ,Humans ,Anaplastic Lymphoma Kinase ,Protein Kinase Inhibitors ,Cell Proliferation ,Dose-Response Relationship, Drug ,Molecular Structure ,Cell growth ,Chemistry ,Drug discovery ,Receptor Protein-Tyrosine Kinases ,Neoplasms, Experimental ,medicine.disease ,In vitro ,ALK inhibitor ,Benzocycloheptenes ,030104 developmental biology ,Biochemistry ,030220 oncology & carcinogenesis ,Focal Adhesion Kinase 1 ,Benzamides ,Cancer research ,Molecular Medicine ,Female ,Drug Screening Assays, Antitumor - Abstract
Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein.
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- 2016
12. Strategies to Mitigate the Bioactivation of 2-Anilino-7-Aryl-Pyrrolo[2,1-f][1,2,4]triazines: Identification of Orally Bioavailable, Efficacious ALK Inhibitors
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Gregory J. Wells, Weihua Wan, Henry J. Breslin, Kevin J. Wells-Knecht, Bruce D. Dorsey, Mark A. Ator, Rabindranath Tripathy, Lisa D. Aimone, Mangeng Cheng, Ashley T. Wohler, Zeqi Huang, Tho V. Thieu, Thelma S. Angeles, Matthew R. Quail, Eugen F. Mesaros, Craig A. Zificsak, James Diebold, Jason C. Wagner, Gregory R. Ott, Lihui Lu, Robert J. McHugh, and Mark S. Albom
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Cytochrome ,Administration, Oral ,Biological Availability ,Antineoplastic Agents ,Mice, SCID ,In Vitro Techniques ,Pharmacology ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,hemic and lymphatic diseases ,Drug Discovery ,Animals ,Anaplastic lymphoma kinase ,Structure–activity relationship ,Anaplastic Lymphoma Kinase ,Pyrroles ,Triazine ,Aniline Compounds ,biology ,Triazines ,Aryl ,Receptor Protein-Tyrosine Kinases ,Biological activity ,Xenograft Model Antitumor Assays ,Rats ,Bioavailability ,chemistry ,Microsomes, Liver ,biology.protein ,Microsome ,Molecular Medicine - Abstract
Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.
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- 2011
13. 2,7-Disubstituted-Pyrrolotriazine Kinase Inhibitors with an Unusually High Degree of Reactive Metabolite Formation
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Gregory R. Ott, Linda Weinberg, Henry J. Breslin, Lisa D. Aimone, Diane E. Gingrich, Kevin J. Wells-Knecht, Mark A. Ator, Gregory J. Wells, Mehran Yazdanian, Eugen F. Mesaros, Zeqi Huang, Kelli S. Zeigler, Bruce D. Dorsey, and Mangeng Cheng
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Spectrometry, Mass, Electrospray Ionization ,Stereochemistry ,Chemistry, Pharmaceutical ,Toxicology ,Mice ,Troglitazone ,chemistry.chemical_compound ,Dogs ,Biotransformation ,medicine ,Animals ,Bile ,Humans ,Pyrroles ,Sulfhydryl Compounds ,Chromans ,Clozapine ,Protein Kinase Inhibitors ,Chromatography, High Pressure Liquid ,chemistry.chemical_classification ,Triazines ,Kinase ,Haplorhini ,General Medicine ,Glutathione ,In vitro ,Rats ,Biochemistry ,chemistry ,Toxicity ,Microsomes, Liver ,Microsome ,Thiol ,Thiazolidinediones ,Protein Kinases ,Chromatography, Liquid ,medicine.drug - Abstract
There are numerous published studies establishing a link between reactive metabolite formation and toxicity of various drugs. Although the correlation between idiosyncratic reactions and reactive metabolite formation is not 1:1, the association between the two is such that many pharmaceutical companies now monitor for reactive metabolites as a standard part of drug candidate testing and selection. The most common method involves in vitro human microsomal incubations in the presence of a thiol trapping agent, such as glutathione (GSH), followed by LC/MS analysis. In this study, we describe several 2,7-disubstituted-pyrrolotriazine analogues that are extremely potent reactive metabolite precursors. Utilizing a UPLC/UV/MS method, unprecedented levels of GSH adducts were measured that are 5-10 times higher than previously reported for high reactive metabolite-forming compounds such as clozapine and troglitazone.
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- 2011
14. CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/Inverse Agonist with Cognition-Enhancing and Wake-Promoting Activities
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Emir Duzic, Edward R. Bacon, Joanne R. Mathiasen, Michael J. Marino, Donna Bozyczko-Coyne, John A. Gruner, John P. Mallamo, Rita Raddatz, Dorothy G. Flood, Lisa D. Aimone, Hervé Schaffhauser, Siyuan Le, Maciej Gasior, Michael Williams, Mark A. Ator, and Robert L. Hudkins
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Pharmacology ,Agonist ,Chemistry ,medicine.drug_class ,Antagonist ,Receptor antagonist ,Dose–response relationship ,chemistry.chemical_compound ,medicine ,Molecular Medicine ,Inverse agonist ,Receptor ,Ex vivo ,Histamine - Abstract
CEP-26401 [irdabisant; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl] is a novel, potent histamine H₃ receptor (H₃R) antagonist/inverse agonist with drug-like properties. High affinity of CEP-26401 for H₃R was demonstrated in radioligand binding displacement assays in rat brain membranes (K(i) = 2.7 ± 0.3 nM) and recombinant rat and human H₃R-expressing systems (K(i) = 7.2 ± 0.4 and 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and inverse agonist activities in [³⁵S]guanosine 5'-O-(γ-thio)triphosphate binding assays. After oral dosing of CEP-26401, occupancy of H₃R was estimated by the inhibition of ex vivo binding in rat cortical slices (OCC₅₀ = 0.1 ± 0.003 mg/kg), and antagonism of the H₃R agonist R-α-methylhistamine- induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED₅₀ = 0.06 mg/kg). CEP-26401 improved performance in the rat social recognition model of short-term memory at doses of 0.01 to 0.1 mg/kg p.o. and was wake-promoting at 3 to 30 mg/kg p.o. In DBA/2NCrl mice, CEP-26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), whereas the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Coadministration of CEP-26401 and risperidone at subefficacious doses (3 and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H₃R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics.
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- 2011
15. 2,7-Disubstituted-pyrrolo[2,1-f][1,2,4]triazines: New Variant of an Old Template and Application to the Discovery of Anaplastic Lymphoma Kinase (ALK) Inhibitors with in Vivo Antitumor Activity
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Mark S. Albom, Bruce D. Dorsey, Joseph G. Lisko, Mangeng Cheng, Bruce Ruggeri, Arup K. Ghose, Eugen F. Mesaros, Weihua Wan, Mark A. Ator, Matthew R. Quail, Zeqi Huang, Diane E. Gingrich, Tho V. Thieu, Gregory J. Wells, Thelma S. Angeles, Gregory R. Ott, Lisa D. Aimone, and Lihui Lu
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Models, Molecular ,Cell Membrane Permeability ,Transplantation, Heterologous ,Antineoplastic Agents ,Mice, SCID ,In Vitro Techniques ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,hemic and lymphatic diseases ,Drug Discovery ,medicine ,Animals ,Humans ,Anaplastic lymphoma kinase ,Structure–activity relationship ,Anaplastic Lymphoma Kinase ,Pyrroles ,Anaplastic large-cell lymphoma ,Triazine ,Sulfonamides ,Triazines ,Chemistry ,Kinase ,Receptor Protein-Tyrosine Kinases ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Rats ,Transplantation ,Diaminopyrimidine ,Biochemistry ,Microsomes, Liver ,Lymphoma, Large-Cell, Anaplastic ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Neoplasm Transplantation - Abstract
A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase (ALK). Importantly, incorporation of appropriate potency and selectivity determinants has led to the discovery of several advanced leads that were orally efficacious in animal models of anaplastic large cell lymphoma (ALCL). A lead inhibitor (30) displaying superior efficacy was identified and in depth in vitro/in vivo characterization will be presented.
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- 2011
16. Discovery and Characterization of 6-{4-[3-(R)-2-Methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (CEP-26401, Irdabisant): A Potent, Selective Histamine H3 Receptor Inverse Agonist
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Gilbert Moachon, Lars J. S. Knutsen, Nadine C. Becknell, Mark A. Ator, Joanne R. Mathiasen, Lisa D. Aimone, Rita Raddatz, Michael J. Marino, Robert L. Hudkins, Michael Williams, Mehran Yazdanian, Edward R. Bacon, John P. Mallamo, Prouty Catherine P, and Ming Tao
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Male ,Pyrrolidines ,Drug Inverse Agonism ,Stereochemistry ,Histamine Antagonists ,Biological Availability ,In Vitro Techniques ,Pharmacology ,Crystallography, X-Ray ,Permeability ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,Histamine receptor ,Dogs ,Pharmacokinetics ,Drug Discovery ,Animals ,Humans ,Receptors, Histamine H3 ,Inverse agonist ,Tissue Distribution ,Receptor ,biology ,Chemistry ,Brain ,Cytochrome P450 ,Stereoisomerism ,Rats ,Pyridazines ,Macaca fascicularis ,Solubility ,Lipophilicity ,Microsomes, Liver ,biology.protein ,Molecular Medicine ,Histamine H3 receptor - Abstract
Optimization of a novel series of pyridazin-3-one histamine H(3) receptor (H(3)R) antagonists/inverse agonists identified 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (8a, CEP-26401; irdabisant) as a lead candidate for potential use in the treatment of attentional and cognitive disorders. 8a had high affinity for both human (K(i) = 2.0 nM) and rat (K(i) = 7.2 nM) H(3)Rs with greater than 1000-fold selectivity over the hH(1)R, hH(2)R, and hH(4)R histamine receptor subtypes and against an in vitro panel of 418 G-protein-coupled receptors, ion channels, transporters, and enzymes. 8a demonstrated ideal pharmaceutical properties for a CNS drug in regard to water solubility, permeability and lipophilicity and had low binding to human plasma proteins. It weakly inhibited recombinant cytochrome P450 isoforms and human ether-a-go-go-related gene. 8a metabolism was minimal in rat, mouse, dog, and human liver microsomes, and it had good interspecies pharmacokinetic properties. 8a dose-dependently inhibited H(3)R agonist-induced dipsogenia in the rat (ED(50) = 0.06 mg/kg po). On the basis of its pharmacological, pharmaceutical, and safety profiles, 8a was selected for preclinical development. The clinical portions of the single and multiple ascending dose studies assessing safety and pharmacokinetics have been completed allowing for the initiation of a phase IIa for proof of concept.
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- 2011
17. Aequorin functional assay for characterization of G-protein-coupled receptors: Implementation with cryopreserved transiently transfected cells
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Beverly P. Holskin, Sheryl L. Meyer, Emmanuel Burgeon, Bruce Jones, Thao Ung, Emir Duzic, Sandra Y. Flores, Mark A. Ator, and Vincent J. Dupriez
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Biophysics ,Aequorin ,Photoprotein ,Digitonin ,CHO Cells ,Transfection ,Biochemistry ,Receptors, G-Protein-Coupled ,law.invention ,Cricetulus ,law ,Cricetinae ,Animals ,Humans ,Receptor ,Molecular Biology ,G protein-coupled receptor ,Cryopreservation ,biology ,Oxotremorine ,Receptor, Muscarinic M1 ,Cell Biology ,Acetylcholine ,Cell biology ,Cell culture ,biology.protein ,Recombinant DNA ,Calcium ,Function (biology) - Abstract
Assay technologies that measure intracellular Ca 2+ release are among the predominant methods for evaluation of GPCR function. These measurements have historically been performed using cell-permeable fluorescent dyes, although the use of the recombinant photoprotein aequorin (AEQ) as a Ca 2+ sensor has gained popularity with recent advances in instrumentation. The requirement of the AEQ system for cells expressing both the photoprotein and the GPCR target of interest has necessitated the labor-intensive development of cell lines stably expressing both proteins. With the goal of streamlining this process, transient transfections were used to either (1) introduce AEQ into cells stably expressing the GPCR of interest or (2) introduce the GPCR into cells stably expressing the AEQ protein, employing the human muscarinic M 1 receptor as a model system. Robust results were obtained from cryopreserved cells prepared by both strategies, yielding agonist and antagonist pharmacology in good agreement with literature values. Good reproducibility was observed between multiple transient transfection events. These results indicate that transient transfection is a viable and efficient method for production of cellular reagents for use in AEQ assays.
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- 2010
18. Preparation and evaluation of peptidic aspartyl hemiacetals as reversible inhibitors of interleukin-l β converting enzyme (ICE)
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Todd L. Graybill, Roland E. Dolle, Mark A. Ator, Robert E. Miller, and Carla T. Helaszek
- Subjects
chemistry.chemical_classification ,Dipeptide ,biology ,Stereochemistry ,Context (language use) ,Tripeptide ,Biochemistry ,Aldehyde ,chemistry.chemical_compound ,chemistry ,Enzyme inhibitor ,Peptide synthesis ,biology.protein ,Hemiacetal ,Semicarbazone - Abstract
Aspartyl aldehyde, Ac-Tyr-Val-Ala-Asp-H 1 (L-709,049), has been reported to be a potent, reversible inhibitor of interleukin-1 beta converting enzyme (ICE) [Thornberry, N.A. et al. (1992) Nature (London) 356, 768-774]. In the context of our own work, we have developed a general synthetic approach to peptidic aspartyl aldehydes. Semicarbazone derivative, H-Asp(Ot-Bu)-Sc 4, was identified as a stable, masked aspartyl aldehyde equivalent. We have used 4 to synthesize a series of mono-, di- and tripeptide aldehydes, and multigram quantities of Ac-Tyr-Val-Ala-Asp-H 1, Ac-Tyr-Val-Lys-Asp-Sc 21 and Ac-Tyr-Val-Lys-Asp-H 2. Biological evaluation of these aspartyl aldehydes and derivatives suggests that the tripeptide scaffold, Z-Val-Ala-Asp, is a peptide scaffold that retains good potency and selectivity for ICE.
- Published
- 2009
19. Mixed-Lineage Kinase 1 and Mixed-Lineage Kinase 3 Subtype-Selective Dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: Optimization, Mixed-Lineage Kinase 1 Crystallography, and Oral in Vivo Activity in 1-Methyl-4-phenyltetrahydropyridine Models
- Author
-
Donna Bozyczko-Coyne, Steven C. Almo, Jean Husten, Michael S. Saporito, Richard W. Scott, Alexander A. Fedorov, Mark A. Ator, Chung Ho Park, Diebold James L, Ming Tao, Thelma S. Angeles, Sheryl L. Meyer, John P. Mallamo, Lisa D. Aimone, Elena V. Fedorov, Kurt A. Josef, Beverly P. Holskin, Robert L. Hudkins, Joanne R. Mathiasen, and John T. Durkin
- Subjects
Models, Molecular ,Magnetic Resonance Spectroscopy ,Molecular model ,Stereochemistry ,Carbazoles ,Administration, Oral ,In Vitro Techniques ,Crystallography, X-Ray ,Mice ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Transferase ,Protein Kinase Inhibitors ,chemistry.chemical_classification ,Molecular Structure ,MAP kinase kinase kinase ,biology ,Chemistry ,MAP Kinase Kinase Kinases ,Pyrrolidinones ,Rats ,Enzyme ,Enzyme inhibitor ,Mitogen-activated protein kinase ,biology.protein ,Molecular Medicine ,Signal transduction - Abstract
The optimization of the dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-one R(2) and R(12) positions led to the identification of the first MLK1 and MLK3 subtype-selective inhibitors within the MLK family. Compounds 14 (CEP-5104) and 16 (CEP-6331) displayed good potency for MLK1 and MLK3 inhibition with a greater than 30- to 100-fold selectivity for related family members MLK2 and DLK. Compounds 14 and 16 were orally active in vivo in a mouse MPTP biochemical efficacy model that was comparable to the first-generation pan-MLK inhibitor 1 (CEP-1347). The MLK1 structure-activity relationships were supported by the first-reported X-ray crystal structure of MLK1 bound with 16.
- Published
- 2008
20. Design, synthesis, and biological evaluation of sulfonyl acrylonitriles as novel inhibitors of cancer metastasis and spread
- Author
-
Courtney L. Scaife, Craig A. Zificsak, Xuegang Lao, Mark A. Ator, Oana Bollt, Bruce D. Dorsey, Yi Shen, Bruce Ruggeri, Joseph G. Lisko, Jill E. Shea, Jay P. Theroff, Scott K. Kuwada, and Xiufen Li
- Subjects
Antineoplastic Agents ,Apoptosis ,Metastasis ,Mice ,Structure-Activity Relationship ,Pancreatic cancer ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,Sulfones ,Cell Proliferation ,Ovarian Neoplasms ,Acrylonitrile ,Dose-Response Relationship, Drug ,Molecular Structure ,Cell growth ,Chemistry ,Cancer ,medicine.disease ,In vitro ,Pancreatic Neoplasms ,Drug Design ,Immunology ,Cancer cell ,Cancer research ,Molecular Medicine ,Female ,HT29 Cells ,Mesothelial Cell - Abstract
The spread of intra-abdominal cancers is a vexing clinical problem for which there is no widely effective treatment. We discovered previously that (2E)-3-[(4-tert-butylphenyl)sulfonyl]acrylonitrile (1) induced cancer cell apoptosis during adhesion to normal mesothelial cells which line the peritoneum. We recently demonstrated that the sulfonylacrylonitrile portion of 1 and hydrophobic aryl substitution were essential for pro-apoptotic activity in cancer cells. Here we synthesized a diverse series of analogues of 1 in order to improve the efficacy and pharmaceutical properties. Analogues and 1 were compared in their ability to cause cancer cell death during adhesion to normal mesothelial cell monolayers. Potent analogues identified in the in vitro assay were validated and found to exhibit improved inhibition of intra-abdominal cancer in two clinically relevant murine models of ovarian and pancreatic cancer spread and metastasis, highlighting their potential clinical use as an adjunct to surgical resection of cancers.
- Published
- 2015
21. Synthesis and structure–activity relationships of novel pyrrolocarbazole lactam analogs as potent and cell-permeable inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)
- Author
-
Robert L. Hudkins, Mark A. Ator, Ron Bihovsky, Gregory J. Wells, and Jean Husten
- Subjects
Models, Molecular ,Cell Membrane Permeability ,Lactams ,Stereochemistry ,Poly ADP ribose polymerase ,Clinical Biochemistry ,Carbazoles ,Pharmaceutical Science ,Poly(ADP-ribose) Polymerase Inhibitors ,Imides ,PC12 Cells ,Biochemistry ,Poly (ADP-Ribose) Polymerase Inhibitor ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Animals ,Structure–activity relationship ,Pyrroles ,Enzyme Inhibitors ,Molecular Biology ,Indole test ,biology ,Chemistry ,Organic Chemistry ,NAD+ ADP-Ribosyltransferase ,Protein Structure, Tertiary ,Rats ,Enzyme inhibitor ,Lactam ,biology.protein ,Molecular Medicine ,NAD+ kinase ,Poly(ADP-ribose) Polymerases - Abstract
A series of novel pyrrolocarbazole lactams was identified as potent PARP-1 inhibitors in vitro and in a PC12 cellular NAD(+) depletion assay. The SAR trends of substituents at the 3-position, as well as the effect of blocking the indole or lactam NH-groups of the template by methylation or formylation, are discussed in relation to molecular modeling studies.
- Published
- 2006
22. Synthesis and structure–activity relationships of novel poly(ADP-ribose) polymerase-1 inhibitors
- Author
-
Mark A. Ator, Gregory J. Wells, Ming Tao, Robert L. Hudkins, Jean Husten, Chung Ho Park, and Ron Bihovsky
- Subjects
Models, Molecular ,Molecular model ,Stereochemistry ,Poly ADP ribose polymerase ,Clinical Biochemistry ,Carbazoles ,Poly (ADP-Ribose) Polymerase-1 ,Pharmaceutical Science ,Poly(ADP-ribose) Polymerase Inhibitors ,Crystallography, X-Ray ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Humans ,Enzyme Inhibitors ,Imide ,Molecular Biology ,chemistry.chemical_classification ,Molecular Structure ,biology ,Organic Chemistry ,NAD+ ADP-Ribosyltransferase ,General Medicine ,In vitro ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
A series of novel pyrrolocarbazoles was synthesized as potential PARP-1 inhibitors. Pyrrolocarbazole 1 was identified as a potent PARP-1 inhibitor (IC50 = 36 nM) from our internal database. Synthesis of analogs around this template with the aid of modeling studies led to the identification of the truncated imide 14. Compound 14 (IC50 = 40 nM), with deleted B-ring, was found to be an equipotent PARP-1 inhibitor.
- Published
- 2006
23. Serendipitous Discovery of a Prodrug of a PARP-1 Inhibitor
- Author
-
Derek Dunn, Sankar Chatterjee, Jean Husten, Mark A. Ator, and Lisa D. Aimone
- Subjects
Pharmacology ,Chemistry ,Poly ADP ribose polymerase ,fungi ,Organic Chemistry ,Carbazoles ,Drug Evaluation, Preclinical ,Phthalimides ,Poly(ADP-ribose) Polymerase Inhibitors ,Prodrug ,Biochemistry ,Rats ,body regions ,Structure-Activity Relationship ,Drug Discovery ,Animals ,Molecular Medicine ,Prodrugs ,Enzyme Inhibitors ,Poly(ADP-ribose) Polymerases ,skin and connective tissue diseases ,Chickens ,Half-Life ,Protein Binding - Abstract
During SAR development of previously reported pyrrolocarbazole 1, a potent PARP-1 inhibitor, compound 14, was discovered serendipitously to be a prodrug of compound 1.
- Published
- 2013
24. From an Atypical Wake-promoting Agent to Potent Histamine-3 Receptor Inverse Agonists
- Author
-
Derek Dunn, Mark A. Ator, Sankar Chatterjee, Edward R. Bacon, and Rita Raddatz
- Subjects
Pharmacology ,Stereochemistry ,Organic Chemistry ,Modafinil ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,medicine ,Molecular Medicine ,Inverse agonist ,Selectivity ,Receptor ,Histamine ,medicine.drug - Abstract
Utilizing atypical wake-promoting agent modafinil (inactive in both rH(3) and hH(3) binding assays) as a launching pad, a series of sulfinyl- and sulfone-derived H(3) receptor inverse agonists were developed. Brain-permeable compound 27, a potent member of the series displayed excellent selectivity against related family members (H(1), H(2), and H(4) receptors).
- Published
- 2013
25. Phosphoregulation of Mixed-Lineage Kinase 1 Activity by Multiple Phosphorylation in the Activation Loop
- Author
-
George Gessner, Beverly P. Holskin, Matthew S. Reed, Jan Pohl, John T. Durkin, Karla K. Kopec, Brian M. Steffy, Chrysanthe M. Spais, Sheryl L. Meyer, Thelma S. Angeles, and Mark A. Ator
- Subjects
Threonine ,Molecular Sequence Data ,CHO Cells ,Protein Serine-Threonine Kinases ,Mitogen-activated protein kinase kinase ,Biochemistry ,Mass Spectrometry ,MAP2K7 ,Cricetinae ,Animals ,Humans ,Amino Acid Sequence ,Phosphorylation ,Serine/threonine-specific protein kinase ,biology ,MAP kinase kinase kinase ,Cyclin-dependent kinase 5 ,Autophosphorylation ,Cyclin-dependent kinase 2 ,JNK Mitogen-Activated Protein Kinases ,MAP Kinase Kinase Kinases ,Molecular biology ,Protein Structure, Tertiary ,Kinetics ,Mutation ,biology.protein ,Cyclin-dependent kinase 9 - Abstract
Mixed-lineage kinase 1 (MLK1) is a mitogen-activated protein kinase kinase kinase capableof activating the c-Jun NH 2 -terminal kinase (JNK) pathway. Full-length MLK1 has 1104 amino acids anda domain structure identical to MLK2 and MLK3. Immunoblot and mass spectrometry show that MLK1is threonine (and possibly serine) phosphorylated in or near the activation loop. A kinase-dead mutant isnot, consistent with autophosphorylation. Mutation to alanine of any of the four serine or threonine residuesin the activation loop reduces both the activity of the recombinant kinase domain and JNK pathwayactivation driven by full-length MLK1 expressed in mammalian cells. Furthermore, the gel mobility ofthe mutant MLK1s is closer to that of the kinase-dead than wild type, consistent with reducedphosphorylation. Thr312 is the key residue: MLK1[T312A] retains only basal activity (about 1-2% ofwild type), and its gel mobility is indistinguishable from kinase-dead. Thr312 does not suffice, however;phosphorylation of multiple sites is necessary for full activation of MLK1. An activation mechanismconsistent with these data involves phosphorylation of multiple sites in the activation loop, withphosphorylation of Thr312 required for full phosphorylation. This mechanism is broadly similar to thatpreviously reported for MLK3 [Leung, I. W., and Lassam, N. (2001) J. Biol. Chem. 276, 1961-1967],but the key residue differs.The mixed-lineage kinases (MLKs)
- Published
- 2004
26. A New Class of Potent Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: Structure−Activity Relationships for a Series of 9-Alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-ones and the Identification of CEP-5214 and Its Dimethylglycine Ester Prodrug Clinical Candidate CEP-7055
- Author
-
Candy Robinson, Lisa D. Aimone, John P. Mallamo, Shi Yang, Jeffry L. Vaught, Craig A. Dionne, Jasbir Singh, Mark A. Ator, Thelma S. Angeles, Bruce Ruggeri, Sheryl L. Meyer, Robert L. Hudkins, Diane E. Gingrich, Mark S. Albom, Mohamed Iqbal, and Reddy Dandu R
- Subjects
Male ,Models, Molecular ,Stereochemistry ,Hemangiosarcoma ,Carbazoles ,Mice, Nude ,Angiogenesis Inhibitors ,Enzyme-Linked Immunosorbent Assay ,In Vitro Techniques ,Rats, Sprague-Dawley ,Mice ,Structure-Activity Relationship ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Prodrugs ,Pyrroles ,Phosphorylation ,Threonine ,Tyrosine ,Cells, Cultured ,Protein kinase C ,biology ,Chemistry ,Sarcosine ,Prodrug ,Vascular Endothelial Growth Factor Receptor-2 ,Rats ,Indenes ,Liver ,Solubility ,Biochemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Female ,Endothelium, Vascular ,Drug Screening Assays, Antitumor ,Tyrosine kinase - Abstract
A series of potent vascular endothelial growth factor R2 (VEGF-R2) tyrosine kinase inhibitors from a new indenopyrrolocarbazole template is reported. The structure-activity relationships for a series of 9-alkoxymethyl-12-(3-hydroxypropyl)indeno[2,1-a]pyrrolo[3,4-c]carbazole-5-ones revealed an optimal R9 substitution with ethoxymethyl 19 (VEGF-R2 IC(50) = 4 nM) and isopropoxymethyl 21 (VEGF-R2 IC(50) = 8 nM) being the most potent inhibitors in the series. The VEGF-R2 activity was reduced appreciably by increasing the size of the R9 alkoxy group or by alpha-methyl branching adjacent to the ring. The combined R9 alkoxymethyl and N12 hydroxypropyl substitutions were required for potent VEGF-R2 activity, and the corresponding thioether analogues were weaker than their ether counterparts. Compound 21 (R9 isopropoxymethyl, CEP-5214) was identified as a potent, low-nanomolar pan inhibitor of human VEGF-R tyrosine kinases, displaying IC(50) values of 16, 8, and 4 nM for VEGF-R1/FLT-1, VEGF-R2/KDR, and VEGF-R3/FLT-4, respectively, with cellular activity equivalent to the isolated enzyme activity. Compound 21 exhibited good selectivity against numerous tyrosine and serine/threonine kinases including PKC, Tie2, TrkA, CDK1, p38, JNK, and IRK. To increase water solubility and oral bioavailability, the N,N-dimethylglycine ester 40 was prepared. In pharmacokinetic studies in mice and rats, increased plasma levels of 21 were observed after oral administration of 40. Compound 21 demonstrated significant in vivo antitumor activity in numerous tumor models and was advanced into phase I clinical trials as the water-soluble N,N-dimethylglycine ester prodrug 40 (CEP-7055).
- Published
- 2003
27. Wake promoting agents: Search for next generation modafinil, lessons learned: Part III
- Author
-
Derek Dunn, Mark A. Ator, John A. Gruner, Edward R. Bacon, Val R. Marcy, Mohamed Iqbal, Greg A. Hostetler, Yin Guo Lin, Lisa D. Aimone, Sankar Chatterjee, and Bruce Jones
- Subjects
Fluorenes ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Modafinil ,Brain ,Pharmaceutical Science ,Pharmacology ,Biochemistry ,Rats ,Part iii ,Neuroprotective Agents ,Wakefulness-Promoting Agents ,Sulfoxides ,Drug Discovery ,medicine ,Animals ,Molecular Medicine ,Benzhydryl Compounds ,Molecular Biology ,Injections, Intraperitoneal ,medicine.drug - Abstract
In searching for a next generation molecule to the novel wake promoting agent modafinil (compound 1), a series of fluorene-derived wakefulness enhancing agents were developed and evaluated in rat. Extensive pharmacokinetic studies of a potent member of the series (compound 15) revealed that the wake promotion activity of the analog was likely due to an active metabolite (compound 3).
- Published
- 2012
28. Serendipity in discovery of proteasome inhibitors
- Author
-
Mark A. Ator, Derek Dunn, Sankar Chatterjee, Jean Husten, and Mohamed Iqbal
- Subjects
Multicatalytic proteinase ,Chemistry ,Peptidomimetic ,Serendipity ,Drug discovery ,Organic Chemistry ,Clinical Biochemistry ,Cancer therapy ,Pharmaceutical Science ,Oxazoline ,Biochemistry ,First generation ,chemistry.chemical_compound ,Proteasome ,Drug Discovery ,Molecular Medicine ,Enzyme Inhibitors ,Proteasome Inhibitors ,Molecular Biology - Abstract
Among its various catalytic activities, the 'chymotrypsin-like' activity of the proteasome, a large multicatalytic proteinase complex has emerged as the focus of drug discovery efforts in cancer therapy. Herein, a series of first generation (2S, 3R)-2-amino-3-hydroxybutyric acid derived proteasome inhibitors that were discovered serendipitously en route to original goal of generating a series of sterically constrained oxazoline derivatives has been reported.
- Published
- 2012
29. Wake-promoting agents: Search for next generation modafinil: Part II
- Author
-
Derek, Dunn, Greg, Hostetler, Mohamed, Iqbal, Patricia, Messina-McLaughlin, Alyssa, Reiboldt, Yin Guo, Lin, John, Gruner, Edward R, Bacon, Mark A, Ator, and Sankar, Chatterjee
- Subjects
Biphenyl Compounds ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Electroencephalography ,Stereoisomerism ,Motor Activity ,Retinoic Acid 4-Hydroxylase ,Biochemistry ,Rats ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,Cytochrome P-450 Enzyme System ,Area Under Curve ,Drug Discovery ,Animals ,Cytochrome P-450 Enzyme Inhibitors ,Molecular Medicine ,Central Nervous System Stimulants ,Wakefulness ,Sleep ,Molecular Biology ,Injections, Intraperitoneal - Abstract
In search of a next generation molecule to modafinil, a novel wake promoting agent, we previously disclosed bi-phenyl derived racemate compound (±)-2 as a new generation of wake-promoting agent. Here we describe the profiles of the individual enantiomers (-)-2 and (+)-2, respectively.
- Published
- 2012
30. Novel poly(ADP-ribose) polymerase-1 inhibitors
- Author
-
Jean Husten, Sankar Chatterjee, Mark A. Ator, and Derek Dunn
- Subjects
Magnetic Resonance Spectroscopy ,Stereochemistry ,Chemistry, Pharmaceutical ,Poly ADP ribose polymerase ,Clinical Biochemistry ,Carbazoles ,Poly (ADP-Ribose) Polymerase-1 ,Pharmaceutical Science ,Antineoplastic Agents ,Poly(ADP-ribose) Polymerase Inhibitors ,Chemical synthesis ,PC12 Cells ,Biochemistry ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Structure-Activity Relationship ,Neoplasms ,Drug Discovery ,Animals ,Humans ,Enzyme Inhibitors ,Imide ,Thiazole ,Molecular Biology ,chemistry.chemical_classification ,biology ,Chemistry ,NAD+ ADP-Ribosyltransferase ,Organic Chemistry ,NAD ,In vitro ,Recombinant Proteins ,Rats ,Thiazoles ,Enzyme ,Models, Chemical ,Enzyme inhibitor ,Drug Design ,biology.protein ,Molecular Medicine ,Indicators and Reagents ,DNA Damage - Abstract
Synthesis and activity of a series of 4-thiazol-yl substituted analogs of novel pyrrolocarbazole 1 as poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors have been disclosed.
- Published
- 2012
31. Mixed lineage kinase activity of indolocarbazole analogues
- Author
-
Joanne R. Mathiasen, Teresa M. O'Kane, Beth Ann McKenna, Robert L. Hudkins, Donna Bozyczko-Coyne, Masami Kaneko, George W. Gessner, Beth Ann Thomas, Mark A. Ator, Thelma S. Angeles, Chikara Murakata, and Michael S. Saporito
- Subjects
Clinical Biochemistry ,Carbazoles ,Pharmaceutical Science ,Indolocarbazole ,Biochemistry ,Chemical synthesis ,Cell Line ,Mice ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,Animals ,Enzyme Inhibitors ,Protein kinase A ,Molecular Biology ,chemistry.chemical_classification ,biology ,Organic Chemistry ,MAP Kinase Kinase Kinases ,In vitro ,Enzyme ,chemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Signal transduction - Abstract
The MLK1-3 activity for a series of analogues of the indolocarbazole K-252a is reported. Addition of 3,9-bis-alkylthiomethyl groups to K-252a results in potent and selective MLK inhibitors. The in vitro and in vivo survival promoting activity of bis-isopropylthiomethyl-K-252a (16, CEP-11004/KT-8138) is reported.
- Published
- 2002
32. Calpain inhibitors based on the quiescent affinity label concept: high rates of calpain inactivation with leaving groups derived from N-hydroxy peptide coupling reagents
- Author
-
Rabindranath Tripathy, John P. Mallamo, and Mark A. Ator
- Subjects
Affinity label ,Clinical Biochemistry ,Pharmaceutical Science ,Peptide ,Cysteine Proteinase Inhibitors ,Biochemistry ,Cathepsin B ,law.invention ,Structure-Activity Relationship ,law ,Drug Discovery ,Humans ,Structure–activity relationship ,Molecular Biology ,chemistry.chemical_classification ,biology ,Calpain ,Organic Chemistry ,Affinity Labels ,Dipeptides ,Recombinant Proteins ,Enzyme ,chemistry ,Enzyme inhibitor ,Drug Design ,biology.protein ,Recombinant DNA ,Molecular Medicine ,Indicators and Reagents ,Oligopeptides - Abstract
A series of irreversible inhibitors of recombinant calpain has been synthesized and their rates of inactivation have been evaluated against calpain and cathepsin B, respectively. The design of the inhibitors was based on the quiescent affinity label concept. By choosing the appropriate affinity group and by employing leaving groups derived from N-hydroxy coupling reagents, good inhibitors of calpain with high rates of inactivation have been identified. However, poor aqueous stability limits their therapeutic utility.
- Published
- 2000
33. P2-achiral, P'-extended α-ketoamide inhibitors of calpain I
- Author
-
Robert Siman, Derek Dunn, Ming Tao, Sankar Chatterjee, Zi-Qiang Gu, Gregory J. Wells, Mark A. Ator, John P. Mallamo, and Ron Bihovsky
- Subjects
Cysteine Endopeptidases ,Stereochemistry ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Chemical synthesis ,Aminoketone ,Drug Discovery ,medicine ,Humans ,Protease Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,biology ,Calpain ,Chemistry ,Organic Chemistry ,Stereoisomerism ,Amides ,Recombinant Proteins ,In vitro ,Enzyme ,Enzyme inhibitor ,biology.protein ,Molecular Medicine - Abstract
A series of potent P2-achiral, P'-extended alpha-ketoamide inhibitors of calpain I is described.
- Published
- 1999
34. P2-proline-derived inhibitors of calpain I
- Author
-
Sankar Chatterjee, Shobha E. Senadhi, Zi-Qiang Gu, Rabindranath Tripathy, Mark A. Ator, and Derek Dunn
- Subjects
Proline ,Clinical Biochemistry ,Pharmaceutical Science ,Cysteine Proteinase Inhibitors ,Biochemistry ,Chemical synthesis ,law.invention ,Structure-Activity Relationship ,law ,Drug Discovery ,Humans ,Molecular Biology ,chemistry.chemical_classification ,biology ,Calpain ,Chemistry ,Organic Chemistry ,Stereoisomerism ,In vitro ,Enzyme ,Enzyme inhibitor ,Benzene derivatives ,biology.protein ,Recombinant DNA ,Molecular Medicine - Abstract
The syntheses and biological activities of a series of calpain I inhibitors, derived from D- and L-Pro, are described.
- Published
- 1998
35. A Sensitive, Continuously Recording Fluorogenic Assay for Calpain
- Author
-
Donna Bozyczko–Coyne, Sheryl L. Meyer, Satish Mallya, Robert Siman, and Mark A. Ator
- Subjects
Tris ,Erythrocytes ,Detergents ,Biophysics ,Naphthalenes ,Sensitivity and Specificity ,Biochemistry ,Substrate Specificity ,chemistry.chemical_compound ,Chaps ,Humans ,Fluorometry ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Chromatography ,Dipeptide ,biology ,Calpain ,Substrate (chemistry) ,Cholic Acids ,Dipeptides ,Cell Biology ,Recombinant Proteins ,Kinetics ,Enzyme ,chemistry ,biology.protein ,Thiol Protease - Abstract
We have developed a sensitive and continuously recording fluorogenic assay for the thiol protease calpain. This assay uses the dipeptide substrate Suc-Leu-Tyr-4-Methoxy-2-Naphthylamine (Suc-LY-MNA) in Tris buffer (pH 7.5) in the presence of 0.1% CHAPS. The assay is linear over a wide range of enzyme concentration and is capable of detecting 10 picomolar calpain making it more sensitive than any previously published method. Moreover, this assay gives a rate that is linear for over ten minutes making it useful for mechanistic studies of inhibitors. This assay can be easily adapted to a 96-well plate format facilitating the large scale screening of inhibitors.
- Published
- 1998
36. <scp>d</scp>-Amino Acid Containing, High-Affinity Inhibitors of Recombinant Human Calpain I
- Author
-
Kurt A. Josef, Donna Bozyczko-Coyne, Zi-Qiang Gu, Sankar Chatterjee, Ming Tao, Rabindranath Tripathy, Ron Bihovsky, Mark A. Ator, Beth Ann McKenna, Shobha E. Senadhi, John P. Mallamo, Teresa M. O'Kane, Satish Mallya, Robert Siman, and Derek Dunn
- Subjects
Aldehyde ,Chemical synthesis ,law.invention ,law ,Drug Discovery ,Tumor Cells, Cultured ,Humans ,Amino Acids ,Enzyme Inhibitors ,Binding site ,chemistry.chemical_classification ,Sulfonamides ,Binding Sites ,biology ,Calpain ,Stereoisomerism ,Dipeptides ,Recombinant Proteins ,In vitro ,Kinetics ,Enzyme ,chemistry ,Biochemistry ,Enzyme inhibitor ,Recombinant DNA ,biology.protein ,Molecular Medicine - Published
- 1998
37. 3-chloro-4-carboxamido-6-arylpyridazines as a non-peptide class of interleukin-1β converting enzyme inhibitor
- Author
-
Carla T. Helaszek, Schmidt Stanley J, Hoyer Denton W, Rinker James M, Tina Morgan Ross, Roland E. Dolle, and Mark A. Ator
- Subjects
chemistry.chemical_classification ,biology ,medicine.drug_class ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Nitro compound ,Pharmaceutical Science ,Carboxamide ,Biochemistry ,Chemical synthesis ,In vitro ,Pyridazine ,chemistry.chemical_compound ,Enzyme ,chemistry ,Mechanism of action ,Enzyme inhibitor ,Drug Discovery ,medicine ,biology.protein ,Molecular Medicine ,medicine.symptom ,Molecular Biology - Abstract
The 3-chloro-4-carboxamido-6-arylpyridazines are a novel class of interleukin-1β converting enzyme (ICE) inhibitor. These agents are irreversible inhibitors with pyridazine 23 possessing a k obs [I] = 355 M−1s−1. A structure-activity relationship for this non-peptide class of compounds and the putative mechanism for irreversible inactivation are described.
- Published
- 1997
38. Subsite requirements for peptide aldehyde inhibitors of human calpain I
- Author
-
Shobha E. Senadhi, Eric Griffith, Sheryl L. Meyer, Rabindranath Tripathy, William Biazzo, Sankar Chatterjee, Kurt A. Josef, Manoj Das, Bruce Dembofsky, Bethany Freed, Ming Tao, Patricia A. Messina, Robert Siman, Derek Dunn, Mark A. Ator, Ron Bihovsky, Mohamed Iqbal, and Donna Bozyczko-Coyne
- Subjects
chemistry.chemical_classification ,Dipeptide ,biology ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Peptide ,Calpain ,Tripeptide ,Biochemistry ,Amino acid ,chemistry.chemical_compound ,Enzyme ,chemistry ,Enzyme inhibitor ,Drug Discovery ,biology.protein ,Molecular Medicine ,Binding site ,Molecular Biology - Abstract
Dipeptide and tripeptide aldehydes have been evaluated as inhibitors of human calpain I. Dipeptide aldehydes are generally equipotent with tripeptide aldehydes. Calpain I possesses a rather stringent requirement for Leu at P2, but accepts a variety of capping groups and amino acids at P1 and P3. Several new peptide aldehydes that are more potent than previously reported calpain I inhibitors have been identified.
- Published
- 1997
39. α-((Tetronoyl)oxy)- and α-((tetramoyl)oxy)methyl ketone inhibitors of the interleukin-1β converting enzyme (ICE)
- Author
-
Prouty Catherine P, Roland E. Dolle, Joost Strastes, Mark A. Ator, Speier Gary J, Carla T. Helaszek, Hoyer Denton W, Todd L. Graybill, and Joanne Uhl
- Subjects
chemistry.chemical_classification ,Dipeptide ,Ketone ,biology ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Tripeptide ,Biochemistry ,Chemical synthesis ,Cysteine protease ,chemistry.chemical_compound ,chemistry ,Enzyme inhibitor ,Drug Discovery ,biology.protein ,Lactam ,Molecular Medicine ,Molecular Biology ,Lactone - Abstract
Aryl-substituted tetronic acids, tetramic acids, and cyclic β-dicarbonyl moieties were evaluated as leaving groups in the peptidyl-COCH2-X type inhibitor iii. Tripeptidyl aspartyl α-((tetronoyl)oxy)- and α-((tetramoyl)oxy)methyl ketone derivatives demonstrate potent time-dependent inhibition ( k obs [I] 100,000–250,000 M−1s−1) of the cysteine protease ICE.
- Published
- 1997
40. Potent fluoromethyl ketone inhibitors of recombinant human calpain I
- Author
-
Mark A. Ator, Mohamed Iqbal, Kurt A. Josef, Robert Siman, Shobha E. Senadhi, Satish Mallya, John P. Mallamo, Donna Bozyczko-Coyne, Gregory J. Wells, Ron Bihovsky, and Sankar Chatterjee
- Subjects
chemistry.chemical_classification ,Cathepsin ,Proteases ,Ketone ,Dipeptide ,biology ,Tetrahydroisoquinoline ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Calpain ,Biochemistry ,Cathepsin B ,chemistry.chemical_compound ,chemistry ,Cathepsin O ,Drug Discovery ,biology.protein ,Molecular Medicine ,Molecular Biology - Abstract
We report on a series of potent and selective dipeptide fluoromethyl ketone inhibitors of recombinant human calpain I. Compound 4f, having a tetrahydroisoquinoline containing urea motif as N-terminus capping group, is the most potent member ( k obs I = 276,000 M−1 s−1) of this class. This compound was shown to prefer calpain I by >36-fold and approximately 4-fold over the related cysteine proteases, cathepsin B and cathepsin L, respectively.
- Published
- 1996
41. Application of Genetic Algorithms to Combinatorial Synthesis: A Computational Approach to Lead Identification and Lead Optimization
- Author
-
Jasbir Singh, Mark A. Ator, Adi M. Treasurywala, Swapan Chowdhary, Martin P. Allen, James E. Soloweij, David A. Whipple, and Edward P. Jaeger
- Subjects
education.field_of_study ,Meta-optimization ,Chemistry ,Population ,Quality control and genetic algorithms ,General Chemistry ,Combinatorial synthesis ,Biochemistry ,Catalysis ,Identification (information) ,Colloid and Surface Chemistry ,Lead (geology) ,Biological system ,education ,Collagenase activity - Abstract
A genetic algorithms (GA) based strategy is described for the identification or optimization of active leads. This approach does not require the synthesis and evaluation of huge libraries. Instead it involves iterative generations of smaller sample sets, which are assayed, and the “experimentally” determined biological response is used as an input for GA to rapidly find better leads. The GA described here has been applied to the identification of potent and selective stromelysin substrates from a combinatorial-based population of 206 or 64 000 000 possible hexapeptides. Using GA, we have synthesized less then 300 unique immobilized peptides in a total of five generations to achieve this end. The results show that each successive generation provided better and unique substrates. An additional strategy of utilizing the knowledge gained in each generation in a spin-off SAR activity is described here. Sequences from the first generations were evaluated for stromelysin and collagenase activity to identify stro...
- Published
- 1996
42. Synthesis and evaluation of diacylhydrazines as inhibitors of the interleukin-1β converting enzyme (ICE)
- Author
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Todd L. Graybill, Roland E. Dolle, Mark A. Ator, Carla T. Helaszek, and Joost Strasters
- Subjects
Proteases ,Biochemistry ,Stereochemistry ,Chemistry ,Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Interleukin 1β converting enzyme ,Molecular Biology ,Cysteine - Abstract
Diacylhydrazines ([azaAsp 1 ] derivatives) were prepared and shown to inactivate ICE in a time-dependent manner. Inactivation rates for most of these diacylhydrazines were 10-fold slower than their α-substituted methylketone congeners. Rates for 6 and 7 (ca. 18,000 M −1 s −1 ) compared favorably to those reported for Ac-Tyr-Val-Ala-Asp-CH-N 2 and azapeptide inhibitors for other cysteine proteases.
- Published
- 1995
43. Structural and stereochemical requirements of time-dependent inactivators of the interleukin-1β converting enzyme
- Author
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Hoyer Denton W, Schmidt Stanley J, Roland E. Dolle, C. V. C. Prasad, I. Kelly Osifo, Mark A. Ator, Carla T. Helaszek, Prouty Catherine P, Mohamad M. A. Awad, Tina Morgan Ross, Robert E. Miller, Salvino Joseph M, and Todd L. Graybill
- Subjects
chemistry.chemical_classification ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Substrate (chemistry) ,Biochemistry ,Amino acid ,Enzyme ,chemistry ,mental disorders ,Drug Discovery ,Molecular Medicine ,Interleukin 1β converting enzyme ,Molecular Biology - Abstract
Structural and stereochemical requirements of substrate based time-dependent inactivators of interleukin-1β converting enzyme were investigated. Hydrophobic amino acids with L-stereochemistry are preferred at the P 2 and P 3 positions. It appears that both D-and L-Asp are accepted by the enzyme at the P I position.
- Published
- 1995
44. Comparison of LanthaScreen Eu kinase binding assay and surface plasmon resonance method in elucidating the binding kinetics of focal adhesion kinase inhibitors
- Author
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Thelma S. Angeles, Chrysanthe Spais, Jean Husten, Jennifer L. Mason, Mark A. Ator, Mark S. Albom, Sheryl L. Meyer, and Eric Prouty
- Subjects
Drug discovery ,Kinase ,Chemistry ,Surface Plasmon Resonance ,Staurosporine ,Small molecule ,Receptor–ligand kinetics ,Focal adhesion ,Biochemistry ,Focal Adhesion Kinase 1 ,Drug Discovery ,Molecular Medicine ,Humans ,Kinase binding ,Surface plasmon resonance ,Protein Kinase Inhibitors ,Alexa Fluor ,Protein Binding - Abstract
An understanding of the dynamics of drug-target interactions is important in the drug discovery process. Information related to the binding kinetics of a drug toward its target or off-target aids in determining the efficacy or toxicity of a drug. Biophysical techniques such as surface plasmon resonance (SPR) have been available for over 20 years, but have been predominantly utilized to characterize protein-protein interactions. With improvements in instrument sensitivity and data analysis software, interactions between proteins (such as kinases) and small molecules have been successfully evaluated. More recently, the LanthaScreen Eu kinase binding assay for characterizing kinase inhibitors has been described. This assay monitors displacement of an Alexa Fluor 647-labeled tracer from the ATP-binding site of an epitope-tagged kinase by a test compound. Such behavior results in a decrease in time-resolved fluorescence energy transfer signal. In this report, a side-by-side comparison of the LanthaScreen Eu kinase binding assay and the SPR method was performed using inhibitors of focal adhesion kinase. The two methods yielded comparable results and identified compounds with time-dependent inhibition and relatively slow dissociation.
- Published
- 2012
45. A selective, orally bioavailable 1,2,4-triazolo[1,5-a]pyridine-based inhibitor of Janus kinase 2 for use in anticancer therapy: discovery of CEP-33779
- Author
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Matthew A. Curry, Zeqi Huang, Karen L. Milkiewicz, Benjamin J. Dugan, Pawel Dobrzanski, Bruce D. Dorsey, Eugen F. Mesaros, Bruce Ruggeri, Sheryl L. Meyer, Jennifer L. Mason, Mahfuza Jan, Mark S. Albom, Thelma S. Angeles, Diane E. Gingrich, Mark A. Ator, Allison L. Zulli, Lisa D. Aimone, Cynthia Serdikoff, and Kevin J. Wells-Knecht
- Subjects
Models, Molecular ,Pyridines ,Administration, Oral ,Biological Availability ,Mice, Nude ,Antineoplastic Agents ,Pharmacology ,Crystallography, X-Ray ,Cell Line ,Mice ,Structure-Activity Relationship ,Dogs ,hemic and lymphatic diseases ,Drug Discovery ,medicine ,Structure–activity relationship ,Moiety ,Potency ,Transferase ,Animals ,Humans ,Cell potency ,Janus kinase 2 ,biology ,Molecular Structure ,Chemistry ,Cancer ,Janus Kinase 2 ,Triazoles ,medicine.disease ,Xenograft Model Antitumor Assays ,Rats ,biology.protein ,Microsomes, Liver ,Molecular Medicine ,Tyrosine kinase - Abstract
Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure-activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2.
- Published
- 2012
46. Discovery of an orally efficacious inhibitor of anaplastic lymphoma kinase
- Author
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Thelma S. Angeles, Matthew R. Quail, Weihua Wan, Lisa D. Aimone, Matthew A. Curry, Diane E. Gingrich, Mangeng Cheng, R. Curtis Haltiwanger, Arup K. Ghose, Mark S. Albom, Mark A. Ator, Bruce D. Dorsey, Joseph G. Lisko, Kevin J. Wells-Knecht, Bruce Ruggeri, Gregory R. Ott, and Lihui Lu
- Subjects
Models, Molecular ,ERG1 Potassium Channel ,medicine.drug_class ,Morpholines ,Administration, Oral ,Antineoplastic Agents ,Mice, SCID ,Pharmacology ,Piperazines ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Dogs ,In vivo ,hemic and lymphatic diseases ,Cell Line, Tumor ,Drug Discovery ,medicine ,Anaplastic lymphoma kinase ,Animals ,Humans ,Anaplastic Lymphoma Kinase ,Cycloheptanes ,Phosphorylation ,Crizotinib ,biology ,Dose-Response Relationship, Drug ,Chemistry ,Kinase ,Cancer ,Receptor Protein-Tyrosine Kinases ,medicine.disease ,Xenograft Model Antitumor Assays ,Ether-A-Go-Go Potassium Channels ,Receptor, Insulin ,Rats ,ALK inhibitor ,Insulin receptor ,Diaminopyrimidine ,Pyrimidines ,biology.protein ,Molecular Medicine ,Lymphoma, Large-Cell, Anaplastic ,Female ,medicine.drug ,Protein Binding - Abstract
Anaplastic lymphoma kinase (ALK) is a pro- mising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhibitor crizotinib. Through a series of targeted modifications on an ALK inhibitor diaminopyrimidine scaffold, our research group has driven improvements in ALK potency, kinase selectivity, and overall pharmaceutical properties. Optimization of this scaff old has led to the identification of a potent and efficacious inhibitor of ALK, 25b .As triking feature of25b over previously described ALK inhibitors is its >600-fold selectivity over insulin receptor (IR), a closely related kinase family member. Most importantly, 25b exhibited dose proportional escalation in rat compared to compound 3 which suffered dose limiting absorption preventing further advancement. Compound 25b exhibited significant in vivo antitumor efficacy when dosed orally in an ALK-positive ALCL tumor xenograft model in SCID mice, warranting further assessment in advanced preclinical models.
- Published
- 2012
47. CEP-32496: a novel orally active BRAF(V600E) inhibitor with selective cellular and in vivo antitumor activity
- Author
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Mangeng Cheng, Kathryn Hunter, Bruce D. Dorsey, Bruce Ruggeri, Dana Gitnick, Martin W. Rowbottom, Pawel Dobrzanski, Michael Williams, Darren E. Insko, Michael F. Gardner, Merryl Cramer, Ruwanthi N. Gunawardane, Susan Jones-Bolin, Mehran Yazdanian, Raffaella Faraoni, Julius L. Apuy, Shripad S. Bhagwat, Mark W. Holladay, Robert C. Armstrong, Hugh Zhao, Joyce James, Ronald R. Nepomuceno, and Mark A. Ator
- Subjects
Sorafenib ,Male ,Proto-Oncogene Proteins B-raf ,Cancer Research ,Colorectal cancer ,Administration, Oral ,Mice, Nude ,Antineoplastic Agents ,Pharmacology ,Rats, Sprague-Dawley ,Mice ,Dogs ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Vemurafenib ,neoplasms ,Cell Proliferation ,business.industry ,Kinase ,Melanoma ,Phenylurea Compounds ,Cancer ,medicine.disease ,digestive system diseases ,Rats ,Macaca fascicularis ,Oncology ,Quinazolines ,Drug Screening Assays, Antitumor ,business ,V600E ,medicine.drug - Abstract
Mutations in the BRAF gene have been identified in approximately 7% of cancers, including 60% to 70% of melanomas, 29% to 83% of papillary thyroid carcinomas, 4% to 16% colorectal cancers, and a lesser extent in serous ovarian and non–small cell lung cancers. The V600E mutation is found in the vast majority of cases and is an activating mutation, conferring transforming and immortalization potential to cells. CEP-32496 is a potent BRAF inhibitor in an in vitro binding assay for mutated BRAFV600E (Kd BRAFV600E = 14 nmol/L) and in a mitogen-activated protein (MAP)/extracellular signal–regulated (ER) kinase (MEK) phosphorylation (pMEK) inhibition assay in human melanoma (A375) and colorectal cancer (Colo-205) cell lines (IC50 = 78 and 60 nmol/L). In vitro, CEP-32496 has multikinase binding activity at other cancer targets of interest; however, it exhibits selective cellular cytotoxicity for BRAFV600E versus wild-type cells. CEP-32496 is orally bioavailable in multiple preclinical species (>95% in rats, dogs, and monkeys) and has single oral dose pharmacodynamic inhibition (10–55 mg/kg) of both pMEK and pERK in BRAFV600E colon carcinoma xenografts in nude mice. Sustained tumor stasis and regressions are observed with oral administration (30–100 mg/kg twice daily) against BRAFV600E melanoma and colon carcinoma xenografts, with no adverse effects. Little or no epithelial hyperplasia was observed in rodents and primates with prolonged oral administration and sustained exposure. CEP-32496 benchmarks favorably with respect to other kinase inhibitors, including RAF-265 (phase I), sorafenib, (approved), and vemurafenib (PLX4032/RG7204, approved). CEP-32496 represents a novel and pharmacologically active BRAF inhibitor with a favorable side effect profile currently in clinical development. Mol Cancer Ther; 11(4); 930–41. ©2012 AACR.
- Published
- 2012
48. σRecognition sites in brain and peripheral tissues Characterization and effects of cytochrome P450 inhibitors
- Author
-
Diane L. DeHaven-Hudkins, Lorraine F. Lanyon, Mark A. Ator, and Felicia Y. Ford-Rice
- Subjects
Male ,Pentazocine ,Cytochrome ,Guinea Pigs ,Guanidines ,Biochemistry ,Guinea pig ,Cytochrome P-450 Enzyme System ,Testis ,medicine ,Animals ,Cytochrome P-450 Enzyme Inhibitors ,Enzyme inducer ,Binding site ,Pharmacology ,Binding Sites ,biology ,Chemistry ,Brain ,Cytochrome P450 ,Heart ,Biological activity ,Rats ,Isoenzymes ,Liver ,biology.protein ,Microsome ,Subcellular Fractions ,medicine.drug - Abstract
Binding to sigma sites in subcellular fractions of brain and in crude homogenates from peripheral tissues of the guinea pig was characterized with the [3H]ligands (+)pentazocine and di(2-tolyl)guanidine (DTG). The inhibitory effects of representative sigma compounds and cytochrome P450 inhibitors were evaluated in guinea pig tissues, and the effects of cytochrome P450 induction on sigma binding in the rat were investigated. For both ligands, the majority of sites were localized to the microsomal fractions. The KD values for [3H](+)pentazocine- or [3H]DTG-labeled sigma sites in guinea pig liver and testes were 2-fold lower than those in brain and heart. The number of sites labeled by [3H](+)pentazocine varied, with an order of livertestesbrainheart. In contrast, the Bmax values for [3H]DTG-defined sigma sites were greatest in testes, followed by liver, brain and heart. The rank order of potency for representative sigma and P450 compounds was similar in brain, liver and testes for both [3H]ligands, and the potency of selective compounds to displace sigma binding in guinea pig liver failed to correlate with their abilities to inhibit cytochrome P450IID1 activity in human liver. Following induction of cytochrome P450IIB1 with phenobarbital or cytochrome P450IA1 with beta-naphthoflavone, neither the affinity nor the number of sigma sites was altered in rat brain or liver. These results suggest that sigma sites in the periphery are similar to those in the brain, and that the sigma binding site is not identical with cytochrome P450IIB1, P450IA1 or P450IID1.
- Published
- 1994
49. CEP-28122, a highly potent and selective orally active inhibitor of anaplastic lymphoma kinase with antitumor activity in experimental models of human cancers
- Author
-
Giorgio Inghirami, Lisa D. Aimone, Mangeng Cheng, Bruce D. Dorsey, Weihua Wan, Thelma S. Angeles, Bruce Ruggeri, Mark A. Ator, Diane E. Gingrich, Cristina Abele, Matthew R. Quail, Gregory E Ott, Rodolfo Machiorlatti, Mark S. Albom, Flavio Cristofani, and Lihui Lu
- Subjects
Cancer Research ,Lung Neoplasms ,medicine.drug_class ,Immunoblotting ,Administration, Oral ,Biological Availability ,Mice, Nude ,Antineoplastic Agents ,Mice, SCID ,Pharmacology ,Biology ,chemistry.chemical_compound ,Mice ,Neuroblastoma ,Mice, Inbred NOD ,hemic and lymphatic diseases ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Neoplasms ,medicine ,Anaplastic lymphoma kinase ,Animals ,Humans ,Anaplastic Lymphoma Kinase ,Cytotoxicity ,Protein Kinase Inhibitors ,Cell Proliferation ,Mice, Knockout ,Dose-Response Relationship, Drug ,Molecular Structure ,Receptor Protein-Tyrosine Kinases ,Tyrosine phosphorylation ,medicine.disease ,Xenograft Model Antitumor Assays ,Lymphoma ,ALK inhibitor ,Benzocycloheptenes ,Pyrimidines ,Oncology ,chemistry ,Cell culture ,Female ,Lymphoma, Large B-Cell, Diffuse ,Growth inhibition ,Interleukin Receptor Common gamma Subunit - Abstract
Anaplastic lymphoma kinase (ALK) is constitutively activated in a number of human cancer types due to chromosomal translocations, point mutations, and gene amplification and has emerged as an excellent molecular target for cancer therapy. Here we report the identification and preclinical characterization of CEP-28122, a highly potent and selective orally active ALK inhibitor. CEP-28122 is a potent inhibitor of recombinant ALK activity and cellular ALK tyrosine phosphorylation. It induced concentration-dependent growth inhibition/cytotoxicity of ALK-positive anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer (NSCLC), and neuroblastoma cells, and displayed dose-dependent inhibition of ALK tyrosine phosphorylation in tumor xenografts in mice, with substantial target inhibition (>90%) for more than 12 hours following single oral dosing at 30 mg/kg. Dose-dependent antitumor activity was observed in ALK-positive ALCL, NSCLC, and neuroblastoma tumor xenografts in mice administered CEP-28122 orally, with complete/near complete tumor regressions observed following treatment at doses of 30 mg/kg twice daily or higher. Treatment of mice bearing Sup-M2 tumor xenografts for 4 weeks and primary human ALCL tumor grafts for 2 weeks at 55 or 100 mg/kg twice daily led to sustained tumor regression in all mice, with no tumor reemergence for more than 60 days postcessation of treatment. Conversely, CEP-28122 displayed marginal antitumor activity against ALK-negative human tumor xenografts under the same dosing regimens. Administration of CEP-28122 was well tolerated in mice and rats. In summary, CEP-28122 is a highly potent and selective orally active ALK inhibitor with a favorable pharmaceutical and pharmacokinetic profile and robust and selective pharmacologic efficacy against ALK-positive human cancer cells and tumor xenograft models in mice. Mol Cancer Ther; 11(3); 670–9. ©2011 AACR.
- Published
- 2011
50. Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E
- Author
-
Brian T. Campbell, Arup K. Ghose, Helen Hua, Ronald R. Nepomuceno, Joyce James, Mark A. Ator, Brian Struss, Torsten Herbertz, Ruwanthi N. Gunawardane, Mark W. Holladay, Michael Williams, Darren E. Insko, Eduardo Setti, Susan Jones-Bolin, Ianina Valenta, Julius L. Apuy, Sunny Abraham, Martin W. Rowbottom, Michael F. Gardner, Robert C. Armstrong, Merryl D. Cramer, Michael Gibney, Lan Tran, Kelly G. Sprankle, Maiko Ezawa, Bruce D. Dorsey, Raffaella Faraoni, Dana Gitnick, Shripad Bhagwat, Qi Chao, Andiliy G. Lai, and Bruce Ruggeri
- Subjects
MAPK/ERK pathway ,Male ,Models, Molecular ,Proto-Oncogene Proteins B-raf ,Transplantation, Heterologous ,Administration, Oral ,Mice, Nude ,Pharmacology ,Binding, Competitive ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,Dogs ,Cell Line, Tumor ,Drug Discovery ,Quinazoline ,Structure–activity relationship ,Animals ,Humans ,Protein kinase A ,Cell Proliferation ,Cell growth ,Phenylurea Compounds ,Stereoisomerism ,Isoxazoles ,digestive system diseases ,Rats ,Transplantation ,Macaca fascicularis ,chemistry ,Mutation ,Cancer research ,Microsomes, Liver ,Quinazolines ,Molecular Medicine ,Female ,Signal transduction ,Drug Screening Assays, Antitumor ,V600E ,Neoplasm Transplantation - Abstract
The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAF(V600E) results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAF(V600E) inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAF(V600E)-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAF(V600E) versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAF(V600E)-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.
- Published
- 2011
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