Discovery of CBPD-409 as a Highly Potent, Selective, and Orally Efficacious CBP/p300 PROTAC Degrader for the Treatment of Advanced Prostate Cancer

  • J Med Chem. 2024 Mar 26. doi: 10.1021/acs.jmedchem.3c01789.
Zhixiang Chen  1 ,  Mi Wang  1 ,  Dimin Wu  1 ,  Lijie Zhao  1 ,  Hoda Metwally  1 ,  Wei Jiang  1 ,  Yu Wang  1 ,  Longchuan Bai  1 ,  Donna McEachern  1 ,  Jie Luo  2 ,  Meilin Wang  3 ,  Qiuxia Li  3 ,  Aleksas Matvekas  3 ,  Bo Wen  3 ,  Duxin Sun  3 ,  Arul M Chinnaiyan  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. Michigan Center for Translational Pathology, Department of Pathology, Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
  • 3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 38530938 DOI: 10.1021/acs.jmedchem.3c01789
Abstract

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.

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