Discovery of CBPD-268 as an Exceptionally Potent and Orally Efficacious CBP/p300 PROTAC Degrader Capable of Achieving Tumor Regression

  • J Med Chem. 2024 Mar 13. doi: 10.1021/acs.jmedchem.3c02124.
Zhixiang Chen  1 ,  Mi Wang  1 ,  Dimin Wu  1 ,  Longchuan Bai  1 ,  Tianfeng Xu  1 ,  Hoda Metwally  1 ,  Yu Wang  1 ,  Donna McEachern  1 ,  Lijie Zhao  1 ,  Ruiting Li  2 ,  John Takyi-Williams  2 ,  Meilin Wang  2 ,  Lu Wang  2 ,  Qiuxia Li  2 ,  Bo Wen  2 ,  Duxin Sun  2 ,  Shaomeng Wang  1
Affiliations
  • 1. 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.
  • 2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 38477974 DOI: 10.1021/acs.jmedchem.3c02124
Abstract

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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