12 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. 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
10. 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
11. Design, synthesis, and biological evaluation of sulfonyl acrylonitriles as novel inhibitors of cancer metastasis and spread
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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
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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.
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- 2015
12. Abstract LB-99: Identification and characterization of small molecule thieno[3,2-d]pyrimidine inhibitors of Protein Kinase C iota (PKCι)
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Christelle Soudy, Bruce D. Dorsey, Philippe Riou, Neil Q. McDonald, Emma Stanway, Bruce Ruggeri, Mark A. Ator, Andrew P. Turnbull, Sven Kjaer, Bhavisha A Patel, Leon Pang, Mark Linch, Jon Roffey, P.J. Owen, Greg R. Ott, Michelle Barnard, Peter J. Parker, Christian Dillon, and Caroline Barton
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Cancer Research ,Oncology ,Biochemistry ,Oncogene ,Kinase ,Cell growth ,Cellular polarity ,PKCS ,Cancer research ,PKN3 ,Signal transduction ,Biology ,Protein kinase C - Abstract
We describe a novel series of small molecule ATP-competitive inhibitors of the atypical class of Protein Kinase C (PKC). The PKC family of serine/threonine kinases are divided into four structurally and functionally distinct sub-types: classic (PKCα, PKCβ, PKCγ); novel (PKCδ, PKCε, PKCη, PKCθ); atypical (PKCι,PKCζ); and PKNs (PKN1, PKN2, PKN3). The PKCs have been defined as key regulators in a multitude of signal transduction pathways that impinge on diverse cellular processes such as proliferation, differentiation, and survival. The regulation and functions of the atypical PKCs are distinct from the classic and novel PKCs.Both atypical isoforms have been implicated in various models of cancer, and PKCι in particular has been described as a potential oncogene. Its abundance is frequently increased, primarily through PKCι gene amplification, in many epithelial tumours including: subsets of squamous non-small cell lung carcinoma, serous ovarian carcinoma, and squamous esophageal carcinoma. It has been widely demonstrated that deregulation of PKCι signalling leads to unconstrained cell growth, increased migratory and invasive behaviour, and aberrant cellular polarity, which is a hallmark of aggressive cancers. Together, these data make a strong case for the inhibition of PKCι as a novel therapeutic strategy. We have discovered a series of ATP-competitive thieno[3,2-d]pyrimidine- based PKCι inhibitors from a high throughput screen. Using structure-based design we have optimized the series and demonstrated potent and selective inhibition of PKCι in biochemical and cellular models. The biochemical, structural, and cellular characterization of these compounds will be described herein. Citation Format: Christelle Soudy, Emma Stanway, Bhavisha Patel, Caroline Barton, Michelle Barnard, Leon Pang, Paul Owen, Andrew Turnbull, Bruce A. Ruggeri, Bruce D. Dorsey, Mark A. Ator, Greg R. Ott, Mark Linch, Philippe Riou, Peter J. Parker, Sven Kjaer, Christian Dillon, Neil Q. McDonald, Jon Roffey. Identification and characterization of small molecule thieno[3,2-d]pyrimidine inhibitors of Protein Kinase C iota (PKCι). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-99. doi:10.1158/1538-7445.AM2014-LB-99
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- 2014
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