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.

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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, Gamblin SJ

J Med Chem. 2016 Nov 10;59(21):9928-9941. doi: 10.1021/acs.jmedchem.6b01315. Epub 2016 Oct 28.

PubMed ID

27739677 [ View in PubMed

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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 muM, cellular EC50 = 0.032 muM) 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
CPI-1205	Histone-lysine N-methyltransferase EZH2	Protein	Humans	Yes	Inhibitor	Details