Search

Your search keyword '"Cook, Andrew S."' showing total 2 results
Start Over Author "Cook, Andrew S." Topic indoles
2 results on '"Cook, Andrew S."'

1. Identification of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B-Cell Lymphomas.

Author

Vaswani RG, Gehling VS, Dakin LA, Cook AS, Nasveschuk CG, Duplessis M, Iyer P, Balasubramanian S, Zhao F, Good AC, Campbell R, Lee C, Cantone N, Cummings RT, Normant E, Bellon SF, Albrecht BK, Harmange JC, Trojer P, Audia JE, Zhang Y, Justin N, Chen S, Wilson JR, and Gamblin SJ

Subjects
Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Dogs, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Histone Methyltransferases, Histone-Lysine N-Methyltransferase metabolism, Humans, Indoles chemical synthesis, Indoles chemistry, Models, Molecular, Molecular Structure, Neoplasms, Experimental drug therapy, Neoplasms, Experimental pathology, Piperidines chemical synthesis, Piperidines chemistry, Rats, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Clinical Trials, Phase I as Topic, Enzyme Inhibitors pharmacology, Histone-Lysine N-Methyltransferase antagonists & inhibitors, Indoles pharmacology, Lymphoma, B-Cell drug therapy, Piperidines pharmacology
Abstract

Polycomb repressive complex 2 (PRC2) has been shown to play a major role in transcriptional silencing in part by installing methylation marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates with certain malignancies and poor prognosis. EZH2 is the catalytic engine of the PRC2 complex and thus represents a key candidate oncology target for pharmacological intervention. Here we report the optimization of our indole-based EZH2 inhibitor series that led to the identification of CPI-1205, a highly potent (biochemical IC 50 = 0.002 μM, cellular EC 50 = 0.032 μM) and selective inhibitor of EZH2. This compound demonstrates robust antitumor effects in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is currently in Phase I clinical trials. Additionally, we disclose the co-crystal structure of our inhibitor series bound to the human PRC2 complex.

Published
2016
Full Text
View/download PDF

2. Discovery, design, and synthesis of indole-based EZH2 inhibitors.

Author

Gehling VS, Vaswani RG, Nasveschuk CG, Duplessis M, Iyer P, Balasubramanian S, Zhao F, Good AC, Campbell R, Lee C, Dakin LA, Cook AS, Gagnon A, Harmange JC, Audia JE, Cummings RT, Normant E, Trojer P, and Albrecht BK

Subjects
Animals, Antineoplastic Agents chemical synthesis, Cell Line, Tumor, Chemistry Techniques, Synthetic, Drug Design, Drug Discovery, Drug Screening Assays, Antitumor, Drug Stability, Enhancer of Zeste Homolog 2 Protein, HeLa Cells drug effects, Humans, Inhibitory Concentration 50, Mice, Molecular Targeted Therapy methods, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Indoles chemistry, Polycomb Repressive Complex 2 antagonists & inhibitors
Abstract

The discovery and optimization of a series of small molecule EZH2 inhibitors is described. Starting from dimethylpyridone HTS hit (2), a series of indole-based EZH2 inhibitors were identified. Biochemical potency and microsomal stability were optimized during these studies and afforded compound 22. This compound demonstrates nanomolar levels of biochemical potency (IC50=0.002 μM), cellular potency (EC50=0.080 μM), and afforded tumor regression when dosed (200 mpk SC BID) in an EZH2 dependent tumor xenograft model., (Copyright © 2015. Published by Elsevier Ltd.)

Published
2015
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results