2. Academic Validation
  3. Discovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders

Discovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders

  • J Med Chem. 2025 Jan 23;68(2):1113-1133. doi: 10.1021/acs.jmedchem.4c01903.
Lingying Leng 1,  Wenbin Tu 1 2,  Lin Yang 1,  Liyue Huang 1,  Mi Wang 1,  Jennifer L Meagher 3,  Krishnapriya Chinnaswamy 3,  Srinivasa Rao Allu 1,  Rohan Kalyan Rej 1,  Jelena Tošović 1,  Lalgudi Harikrishnan 4,  Zhenwu Li 4,  Zhihua Sui 4,  Jeanne A Stuckey 3 5,  Shaomeng Wang 1 2 6 5
Affiliations

Affiliations

  • 1 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2 Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 SK Life Science Laboratories, 2500 Renaissance Blvd, King of Prussia, Pennsylvania 19406, United States.
  • 5 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 6 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 39745064 DOI: 10.1021/acs.jmedchem.4c01903
Abstract

In the SWI/SNF chromatin-remodeling complex, the mutually exclusive catalytic ATPase subunits SMARCA2 and SMARCA4 proteins have a synthetic-lethal relationship. Selectively targeting SMARCA2 for degradation is a promising and new therapeutic strategy for human cancers harboring inactivated mutated SMARCA4. In this study, we report the design, synthesis, and biological evaluation of novel SMARCA2/4 ligands and our subsequent design of PROTAC degraders using high-affinity SMARCA ligands and VHL-1 ligands. Our efforts led to the discovery of high-affinity SMARCA2/4 bromodomain ligands and the development of a potent and selective SMARCA2 degrader and a highly potent SMARCA2/4 and PBRM1 degrader.

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