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
  • 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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