TNF-α converting enzyme (TACE) inhibitors are promising agents to treat inflammatory disorders and cancer. We have investigated novel tartrate diamide TACE inhibitors where the tartrate core binds to ...zinc in a unique tridentate fashion. Incorporating (
R)-2-(2-
N-alkylaminothiazol-4-yl)pyrrolidines into the left hand side amide of the tartrate scaffold led to the discovery of potent and selective TACE inhibitors, some of which exhibited good rat oral bioavailability.
Abstract 3509
Mutations in the isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) genes are present in ∼16% of acute myeloid leukemia, and cause a neomorphic enzyme activity that results in the ...production of 2-hydroxyglutarate (2HG). Mutational and epigenetic profiling of a large patient cohort of acute myeloid leukemia (AML) has revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and an impaired hematopoietic differentiation. To further investigate the intrinsic effect of 2HG on hematopoietic proliferation and differentiation, we transfected an erythroleukemia cell line (TF-1) with either IDH1 or IDH2 mutant alleles. These cells overexpress the mutant enzyme, have high levels of 2HG, and exhibit GM-CSF independent growth. Consistent with clinical observations, overexpression of the IDH mutant proteins led to hypermethylation of both histones and DNA. These results suggest that mutations in IDH1/2 could lead to epigenetic rewiring of cells that could facilitate the gain of function phenotype. To gain a broader understanding of the biological consequence of the IDH1/2 gain of function mutations we have generated small molecules that are capable of selectively inhibiting IDHm enzymes. Upon compound treatment in vitro, we are able to reverse hypermethylation of both histones and DNA in Idhm expressing cells. These compounds are also suitable for use in vivo and upon compound treatment are able to lower 2HG by >90% in tumor xenograft models. These data suggest that an inhibitor of IDH1/2 mutations could correct the altered gene expression patterns seen in IDH1/2 mutant AML tumors and potentially lead to a profound effect on hematopoietic differentiation, proliferation and tumor growth.
Yen:Agios Pharmaceuticals: Employment, Equity Ownership. Wang:Agios Pharmaceuticals: Employment, Equity Ownership. Schalm:Agios Pharmaceuticals: Employment, Equity Ownership. Hansen:Agios Pharmaceuticals: Employment, Equity Ownership. Straley:Agios Pharmaceuticals: Employment. Kernytsky:Agios Pharmaceuticals: Employment, Equity Ownership. Choe:Agios Pharmaceuticals: Employment, Equity Ownership. Liu:Agios Pharmaceuticals: Employment, Equity Ownership. Popovici-Muller:Agios Pharmaceuticals: Employment, Equity Ownership. Travins:Agios pharmaceuticals: Employment, Equity Ownership. Yang:Agios Pharmaceuticals: Employment, Equity Ownership. Silverman:Agios Pharmaceuticals: Employment, Equity Ownership. Gross:Agios Pharmaceuticals: Employment, Equity Ownership. Dang:Agios Pharmaceuticals: Employment, Equity Ownership. Salituro:Agios Pharmaceuticals: Consultancy, Equity Ownership. Saunders:Agios Pharmaceuticals: Consultancy, Equity Ownership. Dorsch:Agios Pharmaceuticals: Employment, Equity Ownership. Agresta:Agios Pharmaceuticals: Employment. Schenkein:Agios Pharmaceuticals: Employment, Equity Ownership. Su:Agios Pharmaceuticals: Employment, Equity Ownership. Biller:Agios Pharmaceuticals: Employment, Equity Ownership.
Abstract
Cyclin dependent kinase 2 (CDK2) is aberrantly regulated in a wide range of cancers and small molecule inhibitors should be beneficial in the treatment of cancer. Preclinical and clinical ...CDK2 inhibitors are ATP competitive and bind at the ATP site in a canonical mode. A novel binding mode for a new class of quinoline-based inhibitors of CDK2 has been discovered using the affinity-based Automated Ligand Identification System (ALIS) technology. While the inhibitors do bind to the ATP site the key mechanism of action for inhibition is the induction of a novel protein conformational change that enables the compound to bind into the core of the kinase domain. Global changes to CDK2 upon compound binding result in a conformation that can no longer bind to its activating protein cyclin A. Therefore, these inhibitors are both ATP competitive and are protein-protein interaction disrupters. The key strategy for discovering this class of protein-protein disrupter compounds was to screen the unphosphorylated monomer CDK2 in ALIS and to perform secondary binding and enzyme mechanism of action assays that identified quinoline-based compounds that only bound to the inactive CDK2 monomer and not the active CDK2/cyclin A heterodimer. Through a series of chemical modifications the affinity (Ki) of the original hit improved from 0.9 μM to 0.005 μM. The screening strategy utilized and the discovery of this new kinase inhibitor binding mode may be applicable to other kinase programs.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2785. doi:10.1158/1538-7445.AM2011-2785
A series of 4H-pyrazolo1,5-apyrimidin-7-one derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase. A number of these compounds exhibited ...potent activity in enzymatic assay. The synthesis and structure-activity relationship are also described.
Synthesis and optimization of novel tartrate TACE inhibitors are described.
A novel series of TNF-α convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are ...bis-amides of
l-tartaric acid (tartrate) and coordinate to the active site zinc in a tridentate manner. They are selective for TACE over other MMP’s. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (
K
i) as well as excellent activity in ...human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.
The design, synthesis and evaluation of a series of 4
H-Pyrazolo1,5-
apyrimidin-7-ones as potent inhibitors of hepatitis C virus polymerase are described.
A series of 4
H-pyrazolo1,5-
...apyrimidin-7-one derivatives was synthesized and evaluated for inhibitory activity against HCV NS5B RNA-dependent RNA polymerase. A number of these compounds exhibited potent activity in enzymatic assay. The synthesis and structure–activity relationship are also described.
Toward the goal of gaining further insight into carbocation–π interactions, bridged-ring aromatic alkene model systems are being investigated in which one isomer will permit π complexation of an ...intramolecular tertiary carbocation with a benzene ring, but the other isomer will not. The syntheses of three sets of such isomers, having, respectively, benzobicyclo3.2.1octene, benzobicyclo2.2.1heptene, and benzobicyclo4.2.1nonene structures, are described.
Three pairs of isomeric bridged-ring alkenes have been synthesized for planned studies of carbocation–π interaction by comparison of the stabilities of the cations formed by protonation.
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A novel series of TNF-a convertase (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds are bis-amides of l-tartaric acid (tartrate) and coordinate to the active site ...zinc in a tridentate manner. They are selective for TACE over other MMP's. We report the first X-ray crystal structure for a tartrate-based TACE inhibitor.
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