Discovery of SD-436: A Potent, Highly Selective and Efficacious STAT3 PROTAC Degrader Capable of Achieving Complete and Long-Lasting Tumor Regression
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.
Authors
- Renqi Xu
- Chao‐Yie Yang (ORCID: https://orcid.org/0000-0002-5445-0109)
- Meilin Wang (ORCID: https://orcid.org/0000-0003-4509-9561)
- Ranjan Kumar Acharyya (ORCID: https://orcid.org/0000-0002-1562-0216)
- Jeanne A. Stuckey (ORCID: https://orcid.org/0000-0002-4192-8900)
- Jennifer L. Meagher (ORCID: https://orcid.org/0000-0003-1250-4575)
- Krishnapriya Chinnaswamy
- Jelena Tošović (ORCID: https://orcid.org/0000-0001-5531-7193)
- Bo Wen (ORCID: https://orcid.org/0000-0002-8337-220X)
- Longchuan Bai (ORCID: https://orcid.org/0000-0003-1025-2925)
- Donna McEachern (ORCID: https://orcid.org/0000-0001-8662-3425)
- Duxin Sun (ORCID: https://orcid.org/0000-0002-6406-2126)
- Shaomeng Wang (ORCID: https://orcid.org/0000-0002-8782-6950)
- Cai Liu (ORCID: https://orcid.org/0000-0002-4081-0070)
- Mi Wang (ORCID: https://orcid.org/0000-0002-5908-4072)
- Haibin Zhou (ORCID: https://orcid.org/0000-0003-0879-790X)
- Dimin Wu
Institutions
- University of Michigan (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-07
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01946
- Citations
- 19
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 4.44
Funders
- SK Life Science
- Roivant Sciences
- National Institutes of Health
- University of Michigan Comprehensive Cancer Center
- National Cancer Institute