CPI-360 is a potent, selective EZH2inhibitor with IC50 of 0.5 nM and 2.5 nM nM for wt EZH2 and Y641N EZH2, respectively.IC50 value: 0.5 nM, 2.5 nMTarget: EZH2in vitro: CPI-360 functions on the basis of S-adenosyl-Lmethionine(SAM)-competition, inhibits EZH1 about 100-fold less and shows exquisite selectivity across a large panel of histone lysine and arginine, and DNA methyltransferases. CPI-360 potently reduced global H3K27me3 and H3K27me2 levels in a dosedependent manner. CPI-360 effectively suppressed heavy H3K27me3 incorporation in KARPAS-422 cells without affecting total histone turnover. CPI-360 treatment causes time-dependent transcriptional changes in germinal center B cell-like diffuse large B cell lymphoma.in vivo: Twice daily, subcutaneous administration of 200 mg/kg ofCPI-360 reduced tumor growth (TGI 44%) of KARPAS-422 xenografts in mice without affecting body weight or causing any overt adverse effects. CPI-360 completely inhibits EZH2 catalytic activity, since we entirely suppress H3K27me3 turnover over time.
References:
[1]. 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):1463-1475.
[2]. Bruno NC, et al. Design and Preparation of New Palladium Precatalysts for C-C and C-N Cross-Coupling Reactions. Chem Sci. 2013;4:916-920.