CPI-169

CPI-169 is a novel and potent EZH2 inhibitor, with IC50s of 0.24 nM, 0.51 nM, and 6.1 nM for EZH2 WT, EZH2 Y641N, and EZH1, respectively.

Signaling Pathways >> Epigenetics >> Epigenetic Reader Domain

Research Areas >> Cancer

IC50: 0.24 nM (EZH2 WT), 0.51 nM (EZH2 Y641N), 6.1 nM (EZH1)

CPI-169 inhibits the catalytic activity of PRC2 with an IC50 of < 1nM, decreases cellular levels of H3K27me3 with an EC50 of 70 nM, and triggers cell cycle arrest and apoptosis in a variety of cell lines[1]. In KARPAS-422 cells, CPI-169 shows a dose-dependent inhibitory effect on cell viability, and produces synergy anti-proliferative activity when used in combination with ABT-199. In 16 out of 25 NHL cell lines, CPI-169 also suppresses cell growth with GI50 of <5 μM[2].

CPI-169 (200 mpk, s.c. BID) is well tolerated in mice with no observed toxic effect or body weight loss. CPI-169 treatment leads to tumor growth inhibition (TGI) of an EZH2 mutant KARPAS-422 DLBCL xenograft. CPI-169 (100 mpk, BID) with a single dose of CHOP leads tumors to rapidly regress and become unpalpable[1]. In mice bearing KARPAS-422 xenografts, CPI-169 (200 mg/kg, s.c.) effectively suppresses H3K27me3 levels and results in lymphoma tumor regression without affecting body weight or causing any overt adverse effects[2].

[1]. Vidya Balasubramanian, et al. CPI-169, a novel and potent EZH2 inhibitor, synergizes with CHOP in vivoand achieves complete regression in lymphoma xenograft models. Cancer Res October 1, 2014 74; 1697

[2]. Bradley WD, et al. EZH2 inhibitor efficacy in non-Hodgkin's lymphoma does not require suppression of H3K27 monomethylation. Chem Biol. 2014 Nov 20;21(11):1463-75

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