2. Academic Validation
  3. Discovery of Potent, Highly Selective, and Efficacious SMARCA2 Degraders

Discovery of Potent, Highly Selective, and Efficacious SMARCA2 Degraders

  • J Med Chem. 2024 Nov 21. doi: 10.1021/acs.jmedchem.4c01878.
Zhenwu Li 1,  Lalgudi S Harikrishnan 1,  Guozhang Xu 1,  Debangshu Samanta 1,  Jose C Clemente 1,  Lingying Leng 2,  Wenbin Tu 2,  Lin Yang 2,  Liyue Huang 2,  Mi Wang 2,  Shaomeng Wang 2 3 4,  Qiaolin Deng 1,  Elham Behshad 1,  Rakesh Nagilla 1,  Peter Orth 1,  Cory Rice 1,  Corey Strickland 1,  Helai P Mohammad 1,  E Scott Priestley 1,  Zhihua Sui 1
Affiliations

Affiliations

  • 1 SK Life Science Labs, 2500 Renaissance Blvd, King of Prussia, Pennsylvania 19406, United States.
  • 2 Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3 Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 39570797 DOI: 10.1021/acs.jmedchem.4c01878
Abstract

We describe the identification of selective SMARCA2, VHL-based heterobifunctional degraders. Structurally novel indolo[1,2-a]quinazolin-5(7H)-one SMARCA bromodomain Binders were optimized and then converted to SMARCA2 degraders by linking them to well-defined VHL ligands. Our exploration led to the discovery of potent and selective degraders of SMARCA2 over the SMARCA4 paralog, leading to potent and selective growth inhibition of SMARCA4 mutant versus wild type cell lines. We further highlight the optimization of the pharmacokinetic profile of a subset of compounds leading to potent and selective degradation of SMARCA2 in the xenograft model. These compounds provide valuable tools with desirable properties for continued exploration of the biology defining the susceptibility of SMARCA4 mutant cancers to selective loss of SMARCA2.

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