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.

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 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.

• Authors: Rishi G Vaswani, Victor S Gehling, Les A Dakin, Andrew S Cook, Christopher G Nasveschuk, Martin Duplessis, Priyadarshini Iyer, Srividya Balasubramanian, Feng Zhao, Andrew C Good, Robert Campbell, Christina Lee, Nico Cantone, Richard T Cummings, Emmanuel Normant, Steven F Bellon, Brian K Albrecht, Jean-Christophe Harmange, Patrick Trojer, James E Audia, Ying Zhang, Neil Justin, Shuyang Chen, Jon R Wilson, Steven J Gamblin
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 59 Issue 21 Pg. 9928-9941 (11 10 2016) ISSN: 1520-4804 [Electronic] United States
• PMID: 27739677 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Indoles
• Piperidines
• (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
• Histone Methyltransferases
• Histone-Lysine N-Methyltransferase

Topics

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