Discovery of p300 histone acetyltransferase inhibitors bearing an imidazo[4,5-b]pyridine-2-one scaffold for the treatment of multiple myeloma.

Histone acetylation, catalyzed by histone acetyltransferases (HATs), is a critical post-translational modification that regulates diverse cellular processes. p300/CBP, an important family of HATs, has emerged as promising targets for cancer therapy. Herein, we report a series of novel p300 HAT inhibitors based on the lead compound CPI-1612 through structure-based drug design. Among these, compound B6, featuring an imidazo[4,5-b]pyridine-2-one fused-ring scaffold, demonstrates potent in vitro inhibitory activity, with IC50 values of 7 nM against the p300 HAT domain and 8.8 nM in multiple myeloma OPM-2 cells. Treatment with compound B6 suppressed c-Myc expression and decreased H3K18ac/H3K27ac levels in OPM-2 and 22RV1 cells. Furthermore, oral administration of B6 (20 mg/kg) significantly suppressed tumor growth in the OPM-2 xenograft mouse model, achieving a tumor growth inhibition of 60%. Metabolite profiling of B6 provided key insights to guide further rational structural optimization aimed at improving its metabolic stability. Collectively, these findings identify B6 as a highly potent and orally active p300 HAT inhibitor, underscoring its potential as a lead compound for further anticancer drug development.