Precise Conformational Control Yielding Highly Potent and Exceptionally Selective BRD4 Degraders with Strong Antitumor Activity

  • J Med Chem. 2023 Jun 22;66(12):8222-8237. doi: 10.1021/acs.jmedchem.3c00520.
Jiantao Hu  1 ,  Biao Hu  1 ,  Fuming Xu  1 ,  Mi Wang  1 ,  Chong Qin  1 ,  Donna McEachern  1 ,  Jeanne Stuckey  2  3 ,  Shaomeng Wang  1  4  5  3
Affiliations
  • 1. Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2. Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3. Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 37289649 DOI: 10.1021/acs.jmedchem.3c00520
Abstract

Starting from a nonselective bromodomain and extraterminal (BET) inhibitor and a Cereblon Ligand, we have used precise conformational control for the development of two potent and highly selective BRD4 degraders, BD-7148 and BD-9136. These compounds induce rapid degradation of BRD4 protein in cells at concentrations as low as 1 nM and demonstrate ≥1000-fold degradation selectivity over BRD2 or BRD3 protein. Proteomic analysis of >5700 proteins confirmed their highly selective BRD4 degradation. A single dose of BD-9136 selectively and effectively depletes BRD4 protein in tumor tissues for >48 h. BD-9136 effectively inhibits tumor growth without adverse effects on mice and is more efficacious than the corresponding pan BET inhibitor. This study suggests selective degradation of BRD4 as a strategy for the treatment of human cancers and demonstrates a strategy for the design of highly selective PROTAC degraders.

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