A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo
Open accessAbstract
Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Here we report the discovery of SD-36, a small-molecule degrader of STAT3. SD-36 potently induces the degradation of STAT3 protein in vitro and in vivo and demonstrates high selectivity over other STAT members. Induced degradation of STAT3 results in a strong suppression of its transcription network in leukemia and lymphoma cells. SD-36 inhibits the growth of a subset of acute myeloid leukemia and anaplastic large-cell lymphoma cell lines by inducing cell-cycle arrest and/or apoptosis. SD-36 achieves complete and long-lasting tumor regression in multiple xenograft mouse models at well-tolerated dose schedules. Degradation of STAT3 protein, therefore, is a promising cancer therapeutic strategy.
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Targeted STAT3 degradation can completely inhibit the transcriptional activity of both dimerized and monomeric STAT3.
“Second, the targeted STAT3 degradation can completely inhibit the transcriptional activity of both dimerized and monomeric STAT3 (19, 21, 26).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [26]
In Results (“SD-36 is highly potent and specific in suppressing the transcriptional activity of STAT3”; page unavailable), SD-36 completely depleted both monomeric and dimeric STAT3 in MOLM-16 cells and abolished STAT3 DNA binding. The same section reports potent suppression of STAT3 transcriptional activity, but does not establish complete inhibition of transcriptional activity for each form separately. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSD-36 can effectively simulate degradation of STAT3 protein in leukemia cells.
“The PROTAC molecule SD-36 (26), developed by the Wang group with structure-based design, can effectively simulate the degradation of STAT3 protein in leukemia cells.”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [26]
PROTACs afford several advantages for targeting STAT3 over traditional inhibitors.
“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 [26]
Wang et al. developed SD-36, a degrader that targeted STAT3 in leukemia and lymphoma cells.
“In 2019, Wang et al. developed SD-36, a degrader that targeted STAT3 in leukemia and lymphoma cells (26).”
From Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer (2022) · cites this paper as [26]
SD-36 (215) effectively degrades STAT3 protein in xenograft tumor tissue and normal mouse tissue, leading to complete and durable tumor regression in a xenograft tumor model at well-tolerated doses, and induces rapid degradation of STAT3 at low nanomolar concentrations without degrading other STAT proteins.
“SD-36 effectively degraded STAT3 protein in both xenograft tumor tissue and normal mouse tissue, leading to complete and durable tumor regression in a xenograft tumor model at well-tolerated doses. The high specificity of SD-36 for STAT3 was demonstrated as it induced rapid degradation of STAT3 at low nanomolar concentrations in cells and did not degrade other STAT proteins.512”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [512]
PROTACs can overcome drug resistance resulting from mutations of a protein of interest or compensatory increase in protein of interest induced by small molecule inhibitors.
“Third, PROTACs can be used to overcome drug resistance resulting from mutations of a POI or compensatory increase in POI induced by SMIs [3].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [3]
PROTACs can target undruggable or difficult-to-target proteins such as transcription factors and scaffold proteins.
“Second, PROTACs can be developed to target “undruggable” or difficult-to-target proteins such as transcription factors (TFs) and scaffold proteins [3].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [3]
Some PROTACs targeting proteins involved in hematologic malignancies are extremely potent to kill leukemia and cancer cells in vitro.
“Some of them have been shown to be extremely potent to kill leukemia and cancer cells in vitro”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [3]
Some PROTACs targeting proteins involved in hematologic malignancies can achieve complete tumor regression in vivo in animal models.
“and can achieve complete tumor regression in vivo in animal models [3].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [3]
SD-36 effectively degrades mutated STAT3 proteins in tumor cells.
“In addition, SD-36 effectively degraded mutated STAT3 proteins in tumor cells.”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [3]
SD-36 efficiently degrades STAT3 protein in MOLM-16 AML cells and several anaplastic ALCL cell lines (SU-DHL-1, DEL, and KIJK).
“SD-36 efficiently degraded STAT3 protein in MOLM-16 AML cells and several anaplastic ALCL cell lines (SU-DHL-1, DEL, and KIJK).”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [3]
Although SD-36 binds to other STAT proteins such as STAT1 and STAT4, it only degrades STAT3.
“Interestingly, although SD-36 also binds to other STAT proteins, such as STAT1 and STAT4, it only degrades STAT3.”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [3]
SD-36 has desirable PK/PD properties, is well tolerated, and achieves complete and long-lasting tumor regression in mice xenografted with AML and ALCL cell lines.
“Further, SD-36 had desirable PK/pharmacodynamic (PD) properties, was well tolerated and achieved complete and long-lasting tumor regression in mice xenografted with AML and ALCL cell lines.”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [3]
STAT3 PROTACs may have limitations in targeting leukemia than lymphoma because SD-36 demonstrates potent activity in five of nine lymphoma cell lines, while showing activity in only one of nine AML cell lines.
“However, STAT3 PROTACs may have some limitations in targeting leukemia than lymphoma, because SD-36 demonstrates potent activity in five of nine lymphoma cell lines, while showing activity in only one of nine AML cell lines [3].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [3]
Profiling changes in global protein expression by proteomics will be helpful to appreciate potential off-target toxicities of PROTACs.
“Therefore, profiling the changes in global protein expression by proteomics will be helpful to appreciate the potential off-target toxicities of PROTACs [3, 4, 43].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [3]
Several PROTACs have shown promising preclinical results in the treatment of hematologic malignancies.
“several PROTACs have shown promising preclinical results in the treatment of hematologic malignancies [3, 4, 44]”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [3]
PROTACs can target undruggable proteins such as transcription factors.
“PROTACs can target undruggable proteins such as transcription factors (TFs).”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [1]
Several other PROTAC drug candidates with promising preclinical data can potentially be tested in clinical trials in the near future.
“In addition, there are several other PROTAC drug candidates with promising preclinical data that can potentially be tested in clinical trials in the near future [1, 35, 40].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [1]
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“Bai L; Zhou H; Xu R; Zhao Y; Chinnaswamy K; McEachern D; Chen J; Yang C-Y; Liu Z; Wang M; Liu L; Jiang H; Wen B; Kumar P; Meagher JL; Sun D; Stuckey JA; Wang S A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo.”
BackgroundPROTAC therapy as a new targeted therapy for lung cancer
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“In spite of the demonstrated efficacy of SD-36, the structure-based design of the PROTAC requires a lengthy trial-and-error process.”
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Destruction of DNA-binding proteins by programmable O’PROTAC: Oligonucleotide-based PROTAC
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- Authors
- Bai, L., Zhou, H., Xu, R., Zhao, Y., Chinnaswamy, K., McEachern, D., Chen, J., Yang, C.-Y., Liu, Z., Wang, M., Liu, L., Jiang, H., Wen, B., Kumar, P., Meagher, J. L., Sun, D., Stuckey, J. A., & Wang, S.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Wang, Shaomeng
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 36
- Issue
- 5
- Pages
- 498-511.e17
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC6880868
- OpenAlex
- W2983017086
- Cited by
- 652
- References
- 94
- Citations by year
- 2026: 93 · 2025: 96 · 2024: 107 · 2023: 87 · 2022: 110 · 2021: 84 · 2020: 69 · 2019: 5 · 2014: 1
- FWCI
- 23.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- National Institutes of Health
- University of Michigan
- U.S. Department of Energy
- Michigan Technology Tri-Corridor (085P1000817)
- National Cancer Institute
- Rogel Cancer Center, University of Michigan (P30 CA046592)
- Michigan Economic Development Corporation
- Argonne National Laboratory (DE-AC02-06CH11357)
- Office of Science
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- STAT3, small-molecule degraders, protein degradation, acute myeloid leukemia, anaplastic large cell lymphoma, leukemia, lymphoma, tumor regression, xenograft models, apoptosis, cell cycle arrest, transcriptional regulatory networks
- MeSH terms
- Animals, Antineoplastic Agents, Female, Humans, Leukemia, Myeloid, Acute, Gene Expression Regulation, Neoplastic, Apoptosis, Lymphoma, Large-Cell, Anaplastic, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Cell Proliferation, STAT3 Transcription Factor, Mice, Cell Cycle Checkpoints, Proteolysis
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