Cited by 253Protein Degradation and InhibitorsCytokine Signaling Pathways and InteractionsChemical Synthesis and Analysis

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Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein

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Zhou, Haibin, Bai, Longchuan, Xu, Renqi, Zhao, Yujun, Chen, Jianyong, McEachern, Donna, Chinnaswamy, Krishnapriya, Wen, Bo, Dai, Lipeng, Kumar, Praveen, Yang, Chao-Yie, Liu, Zhaomin, Wang, Mi, Liu, Liu, Meagher, Jennifer L., Yi, Han, Sun, Duxin, Stuckey, Jeanne A., Wang, Shaomeng·2019·Journal of Medicinal Chemistry

DOI 10.1021/acs.jmedchem.9b01530PMC PMC8848307

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Abstract

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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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: Zhou, Haibin
Bai, Longchuan
Zhao, Yujun
Chen, Jianyong
McEachern, Donna
Wen, Bo
Kumar, Praveen
Yang, Chao-Yie
Liu, Zhaomin
Wang, Mi
Liu, Liu
Meagher, Jennifer L.
Sun, Duxin
Stuckey, Jeanne A.
Wang, Shaomeng
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
DOI: 10.1021/acs.jmedchem.9b01530
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: doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-045 (stm-asf)
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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Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein

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