Discovery of CZL-077 as a potent, selective, and orally active p300/CBP bromodomain inhibitor with improved in vivo antitumor efficacy.

Inhibition of E1A binding protein (p300)/CREB binding protein (CBP) bromodomains (BRDs) represents a promising cancer therapeutic strategy. Herein, we report the discovery of CZL-077, featuring an (R)-2-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl fragment, as a potent and selective p300/CBP BRD inhibitor with increased oral exposure and improved in vivo antitumor activity. CZL-077 shows potent inhibitory activity against p300/CBP BRDs and effectively inhibits cell growth with IC50 values of 0.024 μM and 5.6 μM in OPM-2 and 22RV1 cells, respectively. Meanwhile, it exhibits high selectivity over the BRDs of BET proteins and excellent oral exposure, achieving an AUC value of 8823 h∗ng/mL. Compared to CCS1477, it shows comparable in vivo efficacy in the OPM-2 xenograft model and demonstrates more potent antitumor activity in the 22RV1 xenograft model, with tumor growth inhibition values of 56.2% and 72.8%, respectively. Overall, CZL-077 is a promising candidate for the treatment of human cancer as a p300/CBP BRD inhibitor.