CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation and RNA processing. EZM2302, also called as GSK3359088, is a CARM1 enzymatic activity inhibitor with IC50 value of 6 nM, selective to CARM1 over other histone methyltransferases. Inhibition of CARM1 by EZM2302 is synergistic with SAH. Treatment with EZM2302 <5 μM for 96h led a dose-dependent decrease in methylation of PABP1 with IC50 value of 38 nM and SmB (increased levels of SmBme0) with EC50 value of 18 nM, two well-characterized CARM1 substrates, as well as in multiple aDMA bands with IC50 value of 9nM in RPMI-8226 or NCI-H929 cells. The histone methylation at the putative CARM1 substrates H3R17 and H3R26 were also evaluated by EZM2302. EZM 2302 exhibted anti-proliferative effects on 9 of the tested multiple myeloma cell lines with various IC50 values <100 nM in the 14-day assay. EZM2302 showed oral available and appropriate pharmacokinetic properties in in vivo study. Oral administration of EZM2302, BID, for 21 days, dose-dependently inhibited tumor growth in the RPMI-8226 xenograft model SCID mice at dose of 37.5, 75, 150 and 300 mg/kg with relationship between methyl mark pharmacodynamics (PD) and tumor growth inhibition (TGI) as decrease in methylation at CARM1 substrates observed.
作用机制
EZM2302 binds the arginine pocket of CARM1 and forms a long-lived inhibitory complex with CARM1 in the presence of SAH. It may inhibit CARM1 in competitive manner.
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