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Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia
Journal article   Open access   Peer reviewed

Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia

Zhiyong Liao, Lei Gu, Jenny Vergalli, Samanta A Mariani, Marco De Dominici, Ravi K Lokareddy, Ayush Dagvadorj, Puranik Purushottamachar, Peter A McCue, Edouard Trabulsi, …
Molecular cancer therapeutics, v 14(8), pp 1777-1793
Aug 2015
DOI: https://doi.org/10.1158/1535-7163.MCT-14-0883
PMID: 26026053
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1158/1535-7163.mct-14-0883View
Published, Version of Record (VoR)CC BY V4.0,  Open

Abstract

Animals Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Apoptosis - drug effects Cell Line, Tumor Cluster Analysis Databases, Factual Disease Models, Animal Drug Resistance, Neoplasm Drug Screening Assays, Antitumor Gene Expression Gene Expression Profiling Genes, Reporter Humans Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism Male Mice Models, Molecular Molecular Conformation Phosphorylation Prostatic Neoplasms - drug therapy Prostatic Neoplasms - metabolism Protein Multimerization Quantitative Structure-Activity Relationship Signal Transduction - drug effects Small Molecule Libraries STAT5 Transcription Factor - antagonists & inhibitors STAT5 Transcription Factor - chemistry STAT5 Transcription Factor - metabolism Tissue Culture Techniques Tumor Suppressor Proteins - antagonists & inhibitors Tumor Suppressor Proteins - chemistry Tumor Suppressor Proteins - metabolism Xenograft Model Antitumor Assays
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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#3 Good Health and Well-Being

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Collaboration types
Domestic collaboration
Web of Science research areas
Oncology
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