2. Academic Validation
  3. Discovery of SD-436: A Potent, Highly Selective and Efficacious STAT3 PROTAC Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression

Discovery of SD-436: A Potent, Highly Selective and Efficacious STAT3 PROTAC Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression

  • J Med Chem. 2024 Nov 28;67(22):20495-20513. doi: 10.1021/acs.jmedchem.4c01946.
Renqi Xu 1,  Haibin Zhou 1,  Longchuan Bai 1,  Donna McEachern 1,  Dimin Wu 1,  Ranjan Kumar Acharyya 1,  Mi Wang 1,  Jelena Tošović 1,  Chao-Yie Yang 1,  Krishnapriya Chinnaswamy 2,  Jennifer L Meagher 2,  Jeanne A Stuckey 2 3,  Cai Liu 4,  Meilin Wang 4,  Bo Wen 4,  Duxin Sun 4 3,  Shaomeng Wang 1 5 6 3
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Medical School, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2 Life Sciences Institute, 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, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5 Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 6 Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 39509603 DOI: 10.1021/acs.jmedchem.4c01946
Abstract

STAT3 is an attractive therapeutic target for Cancer and other human diseases. We have previously reported the discovery of potent, selective, and efficacious PROTAC STAT3 degraders SD-36 and SD-91. In this study, we have designed and synthesized a novel series of STAT3 degraders using a new, high-affinity STAT3 ligand with excellent chemical stability and Cereblon ligands. Our efforts led to the discovery of SD-436, a highly potent and selective STAT3 Degrader. A single intravenous administration of SD-436 at 5 mg/kg effectively induces rapid, complete, and durable depletion of STAT3 in mouse native and xenograft tumor tissues. SD-436 achieves complete and long-lasting tumor regression even with a weekly dosing schedule in leukemia and lymphoma xenograft models in mice. SD-436 represents a promising STAT3 Degrader for advanced preclinical development as a new therapy for the treatment of human cancers and other human diseases.

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