Discovery of SMD-6346: A Potent, Selective, and Orally Active SMARCA2 Degrader for Targeting SMARCA4-Deficient Human Cancers

  • J Med Chem. 2026 Jul 9;69(13):15928-15944. doi: 10.1021/acs.jmedchem.6c01093.
Lingying Leng  1 ,  Liyue Huang  1 ,  Wenbin Tu  1  2 ,  Wei Jiang  1 ,  Rohan Kalyan Rej  1 ,  Srinivasa Rao Allu  1 ,  Yu Wang  1 ,  Mi Wang  1 ,  Jelena Tošović  1 ,  Meilin Wang  3 ,  Bo Wen  3 ,  Duxin Sun  3  4 ,  Shaomeng Wang  1  2  4  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. Department of Pharmaceutical Sciences, 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 Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 42334193 DOI: 10.1021/acs.jmedchem.6c01093
Abstract

Selective targeting SMARCA2 by degradation represents a promising new therapeutic strategy for human cancers harboring deficient SMARCA4. Herein we report the discovery of highly potent, selective and oral available SMARCA2 PROTAC degraders, as exemplified by SMD-6346. SMD-6346 achieves DC50 = 3.3 nM and Dmax > 90% against SMARCA2 and only modest activity against SMARCA4 (DC50 > 1000 nM, Dmax = 46%). SMD-6346 potently and effectively inhibits cell growth in SMARCA4-deficient Cancer cell lines and displays minimal cell growth inhibition activity in SMARCA2/4 wild-type Cancer cell lines. SMD-6346 attains an excellent pharmacokinetic profile and 61% oral bioavailability in mice. Daily oral administration of SMD-6346 induces robust SMARCA2 depletion in tumor tissues in mice and significantly inhibits tumor growth in the H838 SMARCA4-deficient xenograft model in mice. SMD-6346 is a promising, orally bioavailable SMARCA2 degrader for further optimization for the development of a new therapy for SMARCA4-deficient human cancers.

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