Zhixiang Chen, Mi Wang, Dimin Wu, Lijie Zhao, Hoda Metwally, Wei Jiang, Yu Wang, Longchuan Bai, Donna McEachern, Jie Luo, Meilin Wang, Qiuxia Li, Aleksas Matvekas, Bo Wen, Duxin Sun, Arul M Chinnaiyan, Shaomeng Wang
CBP/p300 are critical transcriptional coactivators of the androgen receptor (AR) and are promising cancer therapeutic targets. Herein, we report the discovery of highly potent, selective, and orally bioavailable CBP/p300 degraders using the PROTAC technology with CBPD-409 being the most promising compound. CBPD-409 induces robust CBP/p300 degradation with DC50 0.2-0.4 nM and displays strong antiproliferative effects with IC50 1.2-2.0 nM in the VCaP, LNCaP, and 22Rv1 AR+ prostate cancer cell lines. It has a favorable pharmacokinetic profile and achieves 50% of oral bioavailability in mice...
March 26, 2024: Journal of Medicinal Chemistry