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Start Over Author "Atrash B" Journal journal of medicinal chemistry
5 results on '"Atrash B"'

1. 8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.

Author

Bavetsias V, Lanigan RM, Ruda GF, Atrash B, McLaughlin MG, Tumber A, Mok NY, Le Bihan YV, Dempster S, Boxall KJ, Jeganathan F, Hatch SB, Savitsky P, Velupillai S, Krojer T, England KS, Sejberg J, Thai C, Donovan A, Pal A, Scozzafava G, Bennett JM, Kawamura A, Johansson C, Szykowska A, Gileadi C, Burgess-Brown NA, von Delft F, Oppermann U, Walters Z, Shipley J, Raynaud FI, Westaway SM, Prinjha RK, Fedorov O, Burke R, Schofield CJ, Westwood IM, Bountra C, Müller S, van Montfort RL, Brennan PE, and Blagg J

Subjects
Caco-2 Cells, Cell Membrane Permeability, Enzyme Inhibitors pharmacokinetics, Humans, Jumonji Domain-Containing Histone Demethylases chemistry, Jumonji Domain-Containing Histone Demethylases metabolism, Nuclear Proteins chemistry, Nuclear Proteins metabolism, Pyrimidinones pharmacokinetics, Repressor Proteins chemistry, Repressor Proteins metabolism, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Jumonji Domain-Containing Histone Demethylases antagonists & inhibitors, Nuclear Proteins antagonists & inhibitors, Pyrimidinones chemistry, Pyrimidinones pharmacology, Repressor Proteins antagonists & inhibitors
Abstract

We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.

Published
2016
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2. Structure-based design of orally bioavailable 1H-pyrrolo[3,2-c]pyridine inhibitors of mitotic kinase monopolar spindle 1 (MPS1).

Author

Naud S, Westwood IM, Faisal A, Sheldrake P, Bavetsias V, Atrash B, Cheung KM, Liu M, Hayes A, Schmitt J, Wood A, Choi V, Boxall K, Mak G, Gurden M, Valenti M, de Haven Brandon A, Henley A, Baker R, McAndrew C, Matijssen B, Burke R, Hoelder S, Eccles SA, Raynaud FI, Linardopoulos S, van Montfort RL, and Blagg J

Subjects
Administration, Oral, Aniline Compounds administration & dosage, Aniline Compounds chemistry, Biological Availability, Cell Cycle Proteins metabolism, Dose-Response Relationship, Drug, Heterocyclic Compounds, 2-Ring administration & dosage, Heterocyclic Compounds, 2-Ring chemistry, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases metabolism, Protein-Tyrosine Kinases metabolism, Structure-Activity Relationship, Aniline Compounds pharmacology, Cell Cycle Proteins antagonists & inhibitors, Drug Design, Heterocyclic Compounds, 2-Ring pharmacology, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases antagonists & inhibitors
Abstract

The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.

Published
2013
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3. Aurora isoform selectivity: design and synthesis of imidazo[4,5-b]pyridine derivatives as highly selective inhibitors of Aurora-A kinase in cells.

Author

Bavetsias V, Faisal A, Crumpler S, Brown N, Kosmopoulou M, Joshi A, Atrash B, Pérez-Fuertes Y, Schmitt JA, Boxall KJ, Burke R, Sun C, Avery S, Bush K, Henley A, Raynaud FI, Workman P, Bayliss R, Linardopoulos S, and Blagg J

Subjects
Animals, Aurora Kinase A chemistry, Aurora Kinase A metabolism, Aurora Kinase B chemistry, Aurora Kinase B metabolism, Catalytic Domain, Drug Stability, HCT116 Cells, Humans, Imidazoles metabolism, Indoles chemistry, Indoles metabolism, Indoles pharmacology, Isoenzymes antagonists & inhibitors, Isoenzymes chemistry, Isoenzymes metabolism, Male, Mice, Molecular Docking Simulation, Protein Kinase Inhibitors metabolism, Substrate Specificity, Aurora Kinase A antagonists & inhibitors, Aurora Kinase B antagonists & inhibitors, Drug Design, Imidazoles chemistry, Imidazoles pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology
Abstract

Aurora-A differs from Aurora-B/C at three positions in the ATP-binding pocket (L215, T217, and R220). Exploiting these differences, crystal structures of ligand-Aurora protein interactions formed the basis of a design principle for imidazo[4,5-b]pyridine-derived Aurora-A-selective inhibitors. Guided by a computational modeling approach, appropriate C7-imidazo[4,5-b]pyridine derivatization led to the discovery of highly selective inhibitors, such as compound 28c, of Aurora-A over Aurora-B. In HCT116 human colon carcinoma cells, 28c and 40f inhibited the Aurora-A L215R and R220K mutants with IC50 values similar to those seen for the Aurora-A wild type. However, the Aurora-A T217E mutant was significantly less sensitive to inhibition by 28c and 40f compared to the Aurora-A wild type, suggesting that the T217 residue plays a critical role in governing the observed isoform selectivity for Aurora-A inhibition. These compounds are useful small-molecule chemical tools to further explore the function of Aurora-A in cells.

Published
2013
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4. Optimization of imidazo[4,5-b]pyridine-based kinase inhibitors: identification of a dual FLT3/Aurora kinase inhibitor as an orally bioavailable preclinical development candidate for the treatment of acute myeloid leukemia.

Author

Bavetsias V, Crumpler S, Sun C, Avery S, Atrash B, Faisal A, Moore AS, Kosmopoulou M, Brown N, Sheldrake PW, Bush K, Henley A, Box G, Valenti M, de Haven Brandon A, Raynaud FI, Workman P, Eccles SA, Bayliss R, Linardopoulos S, and Blagg J

Subjects
Administration, Oral, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Aurora Kinase A, Aurora Kinase B, Aurora Kinases, Biological Availability, Cell Line, Tumor, Drug Screening Assays, Antitumor, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Female, Humans, Imidazoles chemistry, Imidazoles pharmacology, Male, Mice, Mice, Inbred BALB C, Microsomes, Liver metabolism, Models, Molecular, Mutation, Neoplasm Transplantation, Purines chemistry, Purines pharmacology, Pyrazoles chemistry, Pyrazoles pharmacology, Pyridines chemistry, Pyridines pharmacology, Rats, Rats, Sprague-Dawley, Transplantation, Heterologous, fms-Like Tyrosine Kinase 3 genetics, Antineoplastic Agents chemical synthesis, Imidazoles chemical synthesis, Leukemia, Myeloid, Acute drug therapy, Protein Serine-Threonine Kinases antagonists & inhibitors, Purines chemical synthesis, Pyrazoles chemical synthesis, Pyridines chemical synthesis, fms-Like Tyrosine Kinase 3 antagonists & inhibitors
Abstract

Optimization of the imidazo[4,5-b]pyridine-based series of Aurora kinase inhibitors led to the identification of 6-chloro-7-(4-(4-chlorobenzyl)piperazin-1-yl)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine (27e), a potent inhibitor of Aurora kinases (Aurora-A K(d) = 7.5 nM, Aurora-B K(d) = 48 nM), FLT3 kinase (K(d) = 6.2 nM), and FLT3 mutants including FLT3-ITD (K(d) = 38 nM) and FLT3(D835Y) (K(d) = 14 nM). FLT3-ITD causes constitutive FLT3 kinase activation and is detected in 20-35% of adults and 15% of children with acute myeloid leukemia (AML), conferring a poor prognosis in both age groups. In an in vivo setting, 27e strongly inhibited the growth of a FLT3-ITD-positive AML human tumor xenograft (MV4-11) following oral administration, with in vivo biomarker modulation and plasma free drug exposures consistent with dual FLT3 and Aurora kinase inhibition. Compound 27e, an orally bioavailable dual FLT3 and Aurora kinase inhibitor, was selected as a preclinical development candidate for the treatment of human malignancies, in particular AML, in adults and children.

Published
2012
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5. Imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases: lead optimization studies toward the identification of an orally bioavailable preclinical development candidate.

Author

Bavetsias V, Large JM, Sun C, Bouloc N, Kosmopoulou M, Matteucci M, Wilsher NE, Martins V, Reynisson J, Atrash B, Faisal A, Urban F, Valenti M, de Haven Brandon A, Box G, Raynaud FI, Workman P, Eccles SA, Bayliss R, Blagg J, Linardopoulos S, and McDonald E

Subjects
Administration, Oral, Animals, Aurora Kinase A, Aurora Kinase B, Aurora Kinase C, Aurora Kinases, Biological Availability, Blood Proteins metabolism, Cell Line, Tumor, Drug Screening Assays, Antitumor, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Female, Humans, Imidazoles pharmacokinetics, Imidazoles pharmacology, In Vitro Techniques, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Microsomes, Liver metabolism, Models, Molecular, Neoplasm Transplantation, Protein Binding, Pyridines pharmacokinetics, Pyridines pharmacology, Structure-Activity Relationship, Transplantation, Heterologous, Imidazoles chemical synthesis, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyridines chemical synthesis
Abstract

Lead optimization studies using 7 as the starting point led to a new class of imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases that possessed the 1-benzylpiperazinyl motif at the 7-position, and displayed favorable in vitro properties. Cocrystallization of Aurora-A with 40c (CCT137444) provided a clear understanding into the interactions of this novel class of inhibitors with the Aurora kinases. Subsequent physicochemical property refinement by the incorporation of solubilizing groups led to the identification of 3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole (51, CCT137690) which is a potent inhibitor of Aurora kinases (Aurora-A IC(50) = 0.015 +/- 0.003 muM, Aurora-B IC(50) = 0.025 muM, Aurora-C IC(50) = 0.019 muM). Compound 51 is highly orally bioavailable, and in in vivo efficacy studies it inhibited the growth of SW620 colon carcinoma xenografts following oral administration with no observed toxicities as defined by body weight loss.

Published
2010
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