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

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 co...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2016-11, Vol.59 (21), p.9928-9941
Main Authors: Vaswani, Rishi G, Gehling, Victor S, Dakin, Les A, Cook, Andrew S, Nasveschuk, Christopher G, Duplessis, Martin, Iyer, Priyadarshini, Balasubramanian, Srividya, Zhao, Feng, Good, Andrew C, Campbell, Robert, Lee, Christina, Cantone, Nico, Cummings, Richard T, Normant, Emmanuel, Bellon, Steven F, Albrecht, Brian K, Harmange, Jean-Christophe, Trojer, Patrick, Audia, James E, Zhang, Ying, Justin, Neil, Chen, Shuyang, Wilson, Jon R, Gamblin, Steven J
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Proliferation - drug effects
Clinical Trials, Phase I as Topic
Dogs
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Histone Methyltransferases
Histone-Lysine N-Methyltransferase - antagonists & inhibitors
Histone-Lysine N-Methyltransferase - metabolism
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Lymphoma, B-Cell - drug therapy
Models, Molecular
Molecular Structure
Neoplasms, Experimental - drug therapy
Neoplasms, Experimental - pathology
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacology
Rats
Structure-Activity Relationship
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Summary: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 IC50 = 0.002 μM, cellular EC50 = 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b01315