ArticleJournal of the American Chemical Society2015
Kinase-Independent Small-Molecule Inhibition of JAK-STAT Signaling.
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 35 citations in OpenAlex.
- The deubiquitylating enzyme Fat facets promotes Fat signalling and restricts tissue growth.Nature communications · 2025Article
- Proximal protein landscapes of the type I interferon signaling cascade reveal negative regulation by PJA2.Nature communications · 2024Article
- Roles of USP9X in cellular functions and tumorigenesis (Review).Oncology letters · 2023Review
- Target identification of small molecules: an overview of the current applications in drug discovery.BMC biotechnology · 2023Review
- Hypothesis-generating proteome perturbation to identify NEU-4438 and acoziborole modes of action in the African Trypanosome.iScience · 2022Article
- Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia.Blood cancer discovery · 2022Article
- Small-molecule discovery in the pancreatic beta cell.Current opinion in chemical biology · 2022Review
- Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity.ACS chemical biology · 2022Article
- Small molecule inhibition of deubiquitinating enzyme JOSD1 as a novel targeted therapy for leukemias with mutant JAK2.Leukemia · 2022Article
- Persistence of myelofibrosis treated with ruxolitinib: biology and clinical implications.Haematologica · 2021Review
- IFN‑γ induces apoptosis in human melanocytes by activating the JAK1/STAT1 signaling pathway.Molecular medicine reports · 2020Article
- Article
- Cellular signaling pathways regulating β-cell proliferation as a promising therapeutic target in the treatment of diabetes.Experimental and therapeutic medicine · 2018Review
- Chemical probes and drug leads from advances in synthetic planning and methodology.Nature reviews. Drug discovery · 2018Review
- The immunoproteasome is induced by cytokines and regulates apoptosis in human islets.The Journal of endocrinology · 2017Article
- Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Identification of 1,2,3-triazole derivatives that protect pancreatic β cells against endoplasmic reticulum stress-mediated dysfunction and death through the inhibition of C/EBP-homologous protein expression.Bioorganic & medicinal chemistry · 2016Article
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Authors and funding
26 authors at 3 institutions in 1 country.
Funding
Abstract
Phenotypic cell-based screening is a powerful approach to small-molecule discovery, but a major challenge of this strategy lies in determining the intracellular target and mechanism of action (MoA) for validated hits. Here, we show that the small-molecule BRD0476, a novel suppressor of pancreatic β-cell apoptosis, inhibits interferon-gamma (IFN-γ)-induced Janus kinase 2 (JAK2) and signal transducer and activation of transcription 1 (STAT1) signaling to promote β-cell survival. However, unlike common JAK-STAT pathway inhibitors, BRD0476 inhibits JAK-STAT signaling without suppressing the kinase activity of any JAK. Rather, we identified the deubiquitinase ubiquitin-specific peptidase 9X (USP9X) as an intracellular target, using a quantitative proteomic analysis in rat β cells. RNAi-mediated and CRISPR/Cas9 knockdown mimicked the effects of BRD0476, and reverse chemical genetics using a known inhibitor of USP9X blocked JAK-STAT signaling without suppressing JAK activity. Site-directed mutagenesis of a putative ubiquitination site on JAK2 mitigated BRD0476 activity, suggesting a competition between phosphorylation and ubiquitination to explain small-molecule MoA. These results demonstrate that phenotypic screening, followed by comprehensive MoA efforts, can provide novel mechanistic insights into ostensibly well-understood cell signaling pathways. Furthermore, these results uncover USP9X as a potential target for regulating JAK2 activity in cellular inflammation.
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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.