2. Academic Validation
  3. Discovery of SMD-3040 as a Potent and Selective SMARCA2 PROTAC Degrader with Strong in vivo Antitumor Activity

Discovery of SMD-3040 as a Potent and Selective SMARCA2 PROTAC Degrader with Strong in vivo Antitumor Activity

  • J Med Chem. 2023 Aug 10;66(15):10761-10781. doi: 10.1021/acs.jmedchem.3c00953.
Lin Yang 1,  Wenbin Tu 1 2,  Liyue Huang 2,  Bukeyan Miao 2,  Atsunori Kaneshige 1 2,  Wei Jiang 2 3,  Lingying Leng 2,  Meilin Wang 4,  Bo Wen 4,  Duxin Sun 3 4,  Shaomeng Wang 1 2 5 3
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 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 37523716 DOI: 10.1021/acs.jmedchem.3c00953
Abstract

SMARCA2 is an attractive synthetic lethality target for human cancers with SMARCA4 deficiency. Herein, we report the design, synthesis, and biological evaluation of selective SMARCA2 protein degraders developed using the proteolysis targeting chimera (PROTAC) technology. Our efforts have led to the discovery of a series of potent and selective SMARCA2 degraders, exemplified by SMD-3040. SMD-3040 degrades SMARCA2 protein with a low nanomolar DC50 and Dmax > 90% and demonstrates an excellent degradation selectivity for SMARCA2 protein over SMARCA4 protein. It displays potent cell growth inhibitory activity in a panel of SMARCA4-deficient Cancer cell lines and has much weaker activity in SMARCA4 wild-type Cancer cell lines. SMD-3040 achieves strong tumor growth inhibition in two SMARCA4-deficient xenograft models at well-tolerated dose schedules. Further optimization of SMD-3040 may lead to the discovery of new therapies for the treatment of human cancers with SMARCA4 deficiency.

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