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. A single oral administration of CBPD-409 at 1 mg/kg achieves >95% depletion of CBP/p300 proteins in the VCaP tumor tissue. CBPD-409 exhibits strong tumor growth inhibition and is much more potent and efficacious than two CBP/p300 inhibitors CCS1477 and GNE-049 and the AR antagonist Enzalutamide. CBPD-409 is a promising CBP/p300 degrader for further extensive evaluations for the treatment of advanced prostate cancer and other types of human cancers.
Journal of medicinal chemistry. 2024 Mar 26 [Epub ahead of print]
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
The Rogel Cancer Center, Department of Internal Medicine, Department of Pharmacology, and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States., Michigan Center for Translational Pathology, Department of Pathology, Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States., Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.