ArticleMolecular cancer therapeutics2015
Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia.
Article in Molecular cancer therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers, 1 of them a synthesis that pooled it.
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Who cites it
32 citing papers in PubMed, 1 synthesis or guideline pooled it, 49 citations in OpenAlex.
- Relevance of humanized three-dimensional tumor tissue models: a descriptive systematic literature review.Cellular and molecular life sciences : CMLS · 2020Pooled it
- Update on Structure and Function of SH2 Domains: Mechanisms and Emerging Targeting Strategies.International journal of molecular sciences · 2025Review
- Identification of Active Phytochemicals to Inhibit Signal Transducer and Activator of Transcription 5A (STAT5A) Dimerization for Prostate Cancer Therapy: AnAnti-cancer agents in medicinal chemistry · 2025Article
- Cytokine-mediated CAR T therapy resistance in AML.Nature medicine · 2024Article
- Stat5 induces androgen receptor (Science advances · 2024Article
- Review
- Notch3 restricts metastasis of breast cancers through regulation of the JAK/STAT5A signaling pathway.BMC cancer · 2023Article
- Genomic Mutations of the STAT5 Transcription Factor Are Associated with Human Cancer and Immune Diseases.International journal of molecular sciences · 2022Review
- Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?Cancers · 2021Review
- Review
- Circulating miRNAs can serve as potential diagnostic biomarkers in chronic myelogenous leukemia patients.Leukemia research reports · 2021Article
- JAK/STAT Activation: A General Mechanism for Bone Development, Homeostasis, and Regeneration.International journal of molecular sciences · 2020Review
- Article
- Cytokines, JAK-STAT Signaling and Radiation-Induced DNA Repair in Solid Tumors: Novel Opportunities for Radiation Therapy.The international journal of biochemistry & cell biology · 2020Review
- Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies.Viruses · 2020Review
- The Selectivity of Fosfosal for STAT5b over STAT5a is Mediated by Arg566 in the Linker Domain.Chembiochem : a European journal of chemical biology · 2020Article
- Pharmacological Inhibition of Oncogenic STAT3 and STAT5 Signaling in Hematopoietic Cancers.Cancers · 2020Review
- Stafia-1: a STAT5a-Selective Inhibitor Developed via Docking-Based Screening of in Silico O-Phosphorylated Fragments.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
- Enzalutamide-Induced Feed-Forward Signaling Loop Promotes Therapy-Resistant Prostate Cancer Growth Providing an Exploitable Molecular Target for Jak2 Inhibitors.Molecular cancer therapeutics · 2020Article
- Direct Targeting Options for STAT3 and STAT5 in Cancer.Cancers · 2019Review
Corrections and comments
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Authors and funding
26 authors at 3 institutions in 1 country.
Funding
Abstract
Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic myeloid leukemia (CML). The lead compound inhibitor of Stat5-002 (IST5-002) prevented both Jak2 and Bcr-Abl-mediated phosphorylation and dimerization of Stat5a/b, and selectively inhibited transcriptional activity of Stat5a (IC50 = 1.5μmol/L) and Stat5b (IC50 = 3.5 μmol/L). IST5-002 suppressed nuclear translocation of Stat5a/b, binding to DNA and Stat5a/b target gene expression. IST5-002 induced extensive apoptosis of prostate cancer cells, impaired growth of prostate cancer xenograft tumors, and induced cell death in patient-derived prostate cancers when tested ex vivo in explant organ cultures. Importantly, IST5-002 induced robust apoptotic death not only of imatinib-sensitive but also of imatinib-resistant CML cell lines and primary CML cells from patients. IST5-002 provides a lead structure for further chemical modifications for clinical development for Stat5a/b-driven solid tumors and hematologic malignancies.
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