Discovery of SD-965 as a Potent, Selective, and Efficacious STAT3 PROTAC Degrader

  • J Med Chem. 2026 Apr 9;69(7):8364-8387. doi: 10.1021/acs.jmedchem.5c03767.
Dimin Wu  1 ,  Haibin Zhou  1 ,  Longchuan Bai  1 ,  Ranjan Kumar Acharyya  1 ,  Hoda Metwally  1 ,  Donna McEachern  1 ,  Mi Wang  1 ,  Jelena Tošović  1 ,  Rohan Kalyan Rej  1 ,  Meilin Wang  2 ,  Bo Wen  2 ,  Duxin Sun  2 ,  Shaomeng Wang  1  3  4  5
Affiliations
  • 1. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3. Department of Pharmacology, 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.
  • 5. The Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 41871272 DOI: 10.1021/acs.jmedchem.5c03767
Abstract

Signal transducer and activator of transcription 3 (STAT3) is a promising therapeutic target for human cancers and other human diseases. Herein, we report on the design, synthesis, and evaluation of novel STAT3 PROTAC degraders using high-affinity STAT3 ligands and Cereblon ligands. Our study led to the discovery of SD-965 as a potent, selective, and efficacious STAT3 Degrader. A single intravenous administration of SD-965 effectively induces rapid, complete, and durable depletion of STAT3 protein in mouse native and human xenograft tumor tissues with no depletion of other STAT proteins. SD-965 is capable of achieving tumor regression even with weekly administration in human leukemia and lymphoma xenograft models in mice without any signs of toxicity. SD-965 represents a promising STAT3 Degrader for extensive evaluation for the treatment of human cancers and other human diseases.

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