ArticleProceedings of the National Academy of Sciences of the United States of America2016
Development of potent small-molecule inhibitors to drug the undruggable steroid receptor coactivator-3.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
63 citing papers in PubMed, 94 citations in OpenAlex.
- Prognostic and predictive importance of the estrogen receptor coactivator AIB1 in a randomized trial comparing adjuvant letrozole and tamoxifen therapy in postmenopausal breast cancer: the Danish cohort of BIG 1-98.Breast cancer research and treatment · 2017Trial
- Steroid receptor coactivators: from basic research to translational opportunities.Endocrine reviews · 2026Review
- Beyond KEAP1: The Context-Specific NRF2 Partner Code in Disease and Therapy.Antioxidants (Basel, Switzerland) · 2026Review
- Steroid receptor coactivators in immunity - From function to emerging translational opportunities.The Journal of biological chemistry · 2026Review
- The ULK1-NCOA3 axis restrains de novo lipogenesis and prevents diet-induced steatohepatitis and fibrosis in mice.The Journal of clinical investigation · 2026Article
- NCOA3 as a Key Regulator in Diabetic Cognitive Dysfunction.Molecular neurobiology · 2026Article
- Targeting steroid receptor coactivators for the treatment of benign female reproductive disorders.Endocrine connections · 2025Review
- TRIM24 as a therapeutic target in endocrine treatment-resistant breast cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Lead Compound Development of SRC-3 Inhibitors with Improved Pharmacokinetic Properties and Anticancer Efficacy.Journal of medicinal chemistry · 2024Article
- Inhibition of SRC-3 as a potential therapeutic strategy for aggressive mantle cell lymphoma.PloS one · 2024Article
- Function of Steroid Receptor Coactivators in T Cells and Cancers: Implications for Cancer Immunotherapy.Critical reviews in immunology · 2024Review
- Steroid receptor coactivators in Treg and Th17 cell biology and function.Frontiers in immunology · 2024Review
- Critical Roles of SRC-3 in the Development and Progression of Breast Cancer, Rendering It a Prospective Clinical Target.Cancers · 2023Review
- Ncoa2 Promotes CD8+ T cell-Mediated Antitumor Immunity by Stimulating T-cell Activation via Upregulation of PGC-1α Critical for Mitochondrial Function.Cancer immunology research · 2023Article
- Identification of small-molecule inhibitors against the interaction of RNA-binding protein PSF and its target RNA for cancer treatment.PNAS nexus · 2023Article
- SRC2 controls CD4Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Article
- Significant Association of Estrogen Receptor-β Isoforms and Coactivators in Breast Cancer Subtypes.Current issues in molecular biology · 2023Article
- AIB1/SRC-3/NCOA3 function in estrogen receptor alpha positive breast cancer.Frontiers in endocrinology · 2023Review
- Article
3 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Protein-protein interactions (PPIs) play a central role in most biological processes, and therefore represent an important class of targets for therapeutic development. However, disrupting PPIs using small-molecule inhibitors (SMIs) is challenging and often deemed as "undruggable." We developed a cell-based functional assay for high-throughput screening to identify SMIs for steroid receptor coactivator-3 (SRC-3 or AIB1), a large and mostly unstructured nuclear protein. Without any SRC-3 structural information, we identified SI-2 as a highly promising SMI for SRC-3. SI-2 meets all of the criteria of Lipinski's rule [Lipinski et al. (2001) Adv Drug Deliv Rev 46(1-3):3-26] for a drug-like molecule and has a half-life of 1 h in a pharmacokinetics study and a reasonable oral availability in mice. As a SRC-3 SMI, SI-2 can selectively reduce the transcriptional activities and the protein concentrations of SRC-3 in cells through direct physical interactions with SRC-3, and selectively induce breast cancer cell death with IC50 values in the low nanomolar range (3-20 nM), but not affect normal cell viability. Furthermore, SI-2 can significantly inhibit primary tumor growth and reduce SRC-3 protein levels in a breast cancer mouse model. In a toxicology study, SI-2 caused minimal acute cardiotoxicity based on a hERG channel blocking assay and an unappreciable chronic toxicity to major organs based on histological analyses. We believe that this work could significantly improve breast cancer treatment through the development of "first-in-class" drugs that target oncogenic coactivators.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.