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Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein
Open accessAbstract
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor and an attractive therapeutic target for cancer and other human diseases. Despite 20 years of persistent research efforts, targeting STAT3 has been very challenging. We report herein the structure-based discovery of potent small-molecule STAT3 degraders based upon the proteolysis targeting chimera (PROTAC) concept. We first designed SI-109 as a potent, small-molecule inhibitor of the STAT3 SH2 domain. Employing ligands for cereblon/cullin 4A E3 ligase and SI-109, we obtained a series of potent PROTAC STAT3 degraders, exemplified by SD-36. SD-36 induces rapid STAT3 degradation at low nanomolar concentrations in cells and fails to degrade other STAT proteins. SD-36 achieves nanomolar cell growth inhibitory activity in leukemia and lymphoma cell lines with high levels of phosphorylated STAT3. A single dose of SD-36 results in complete STAT3 protein degradation in xenograft tumor tissue and normal mouse tissues. SD-36 achieves complete and long-lasting tumor regression in the Molm-16 xenograft tumor model at well-tolerated dose-schedules. SD-36 is a potent, selective, and efficacious STAT3 degrader.
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“The application of PROTACs has afforded several advantages for targeting STAT3 over traditional inhibitors (26, 49).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [49]
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Targeted protein degradation: mechanisms, strategies and application
Zhao, L., Zhao, J., Zhong, K., Tong, A., & Jia, D. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00966-4 · Cited by 1,035
PROTACs: past, present and future
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Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy
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Current strategies for the design of PROTAC linkers: a critical review
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Metadata
- Authors
- Zhou, H., Bai, L., Xu, R., Zhao, Y., Chen, J., McEachern, D., Chinnaswamy, K., Wen, B., Dai, L., Kumar, P., Yang, C.-Y., Liu, Z., Wang, M., Liu, L., Meagher, J. L., Yi, H., Sun, D., Stuckey, J. A., & Wang, S.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Wang, Shaomeng
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-11-20
- Volume
- 62
- Issue
- 24
- Pages
- 11280-11300
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC8848307
- OpenAlex
- W2990256176
- Cited by
- 233
- References
- 40
- Citations by year
- 2026: 26 · 2025: 43 · 2024: 31 · 2023: 33 · 2022: 44 · 2021: 28 · 2020: 27
- FWCI
- 8.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P30 CA046592)
- Comprehensive Cancer Center, University of Michigan
- Oncopia Therapeutics Inc.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- STAT3, PROTACs, small-molecule degraders, SH2 domain inhibitors, structure-based drug design, leukemia, lymphoma, xenograft tumor regression, protein degradation
- MeSH terms
- Animals, Antineoplastic Agents, Azocines, Female, Humans, Indoles, Protein Conformation, Tissue Distribution, Tumor Cells, Cultured, Drug Design, Molecular Structure, Leukemia, Myeloid, Acute, Mice, SCID, Apoptosis, Xenograft Model Antitumor Assays, Cell Proliferation, STAT3 Transcription Factor, Mice, Drug Discovery, Proteolysis, Organophosphonates
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