2. Academic Validation
  3. Discovery of SD-965 as a Potent, Selective, and Efficacious STAT3 PROTAC Degrader

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

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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