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

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

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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