2. Academic Validation
  3. Discovery of SMD-3236: A Potent, Highly Selective and Efficacious SMARCA2 Degrader for the Treatment of SMARC4-Deficient Human Cancers

Discovery of SMD-3236: A Potent, Highly Selective and Efficacious SMARCA2 Degrader for the Treatment of SMARC4-Deficient Human Cancers

  • J Med Chem. 2025 Jan 23;68(2):1155-1178. doi: 10.1021/acs.jmedchem.4c01904.
Lin Yang 1,  Wenbin Tu 1 2,  Lingying Leng 1,  Liyue Huang 1,  Wei Jiang 1,  Mi Wang 1,  Yu Wang 1,  Jennifer L Meagher 3,  Krishnapriya Chinnaswamy 3,  Jeanne A Stuckey 3 4,  Meilin Wang 5,  Bo Wen 5,  Duxin Sun 4 5,  Lalgudi Harikrishnan 6,  Corey Strickland 6,  Cory Rice 6,  Peter Orth 6,  Zhihua Sui 6,  Shaomeng Wang 1 2 4 7
Affiliations

Affiliations

  • 1 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 6 SK Life Science Labs, 2500 Renaissance Boulevard, King of Prussia, Pennsylvania 19406, United States.
  • 7 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 39745073 DOI: 10.1021/acs.jmedchem.4c01904
Abstract

SMARCA2 is an attractive synthetic lethal target in human cancers with mutated, inactivated SMARCA4. We report herein the discovery of highly potent and selective SMARCA2 PROTAC degraders, as exemplified by SMD-3236, which was designed using a new, high-affinity SMARCA ligand and a potent VHL-1 ligand. SMD-3236 achieves DC50 < 1 nM and Dmax > 95% against SMARCA2 and >2000-fold degradation selectivity over SMARCA4. SMD-3236 potently inhibits cell growth in a panel of SMARCA4-deficient cell lines and displays minimal activity in SMARCA4 wild-type cell lines. SMD-3236 induces profound and persistent SMARCA2 depletion in tumor tissues for 1 week with a single administration, while sparing SMARCA4 protein. SMD-3236 effectively inhibits tumor growth with weekly administration in the H838 SMARCA4-deficient human Cancer xenograft model at well-tolerated dose schedules. SMD-3236 represents a promising SMARCA2 degrader for extensive evaluation as a new therapy for the treatment of SMARCA4-deficient human cancers.

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