化学
前列腺癌
癌症
药理学
癌症研究
细胞生长
生物利用度
口服
前列腺
表观遗传学
内科学
生物化学
医学
基因
作者
Zhixiang Chen,Mi Wang,Dongsheng Wu,Longchuan Bai,Tianfeng Xu,Hoda Metwally,Yu Wang,Donna McEachern,Lijie Zhao,Ruiting Li,John Takyi-Williams,Meilin Wang,Lu Wang,Qiuxia Li,Bo Wen,Duxin Sun,Shaomeng Wang
标识
DOI:10.1021/acs.jmedchem.3c02124
摘要
CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer and other types of human cancers. Herein, we report the discovery and characterization of CBPD-268 as an exceptionally potent, effective, and orally efficacious PROTAC degrader of CBP/p300 proteins. CBPD-268 induces CBP/p300 degradation in three androgen receptor-positive prostate cancer cell lines, with DC50 ≤ 0.03 nM and Dmax > 95%, leading to potent cell growth inhibition. It has an excellent oral bioavailability in mice and rats. Oral administration of CBPD-268 at 0.3-3 mg/kg resulted in profound and persistent CBP/p300 depletion in tumor tissues and achieved strong antitumor activity in the VCaP and 22Rv1 xenograft tumor models in mice, including tumor regression in the VCaP tumor model. CBPD-268 was well tolerated in mice and rats and displayed a therapeutic index of >10. Taking these results together, CBPD-268 is a highly promising CBP/p300 degrader as a potential new cancer therapy.
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