Document Type
Article
Publication Date
8-1-2015
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.
Recommended Citation
Liao, Zhiyong; Gu, Lei; Vergalli, Jenny; Mariani, Samanta A.; De Dominici, Marco; Lokareddy, Ravi K.; Dagvadorj, Ayush; Purushottamachar, Puranik; McCue, Peter A.; Trabulsi, Edouard J.; Lallas, Costas D.; Gupta, Shilpa; Ellsworth, Elyse; Blackmon, Shauna; Ertel, Adam; Fortina, Paolo; Leiby, Benjamin E.; Xia, Guanjun; Rui, Hallgeir; Hoang, David T.; Gomella, Leonard G; Cingolani, Gino; Njar, Vincent; Pattabiraman, Nagarajan; Calabretta, Bruno; and Nevalainen, Marja T., "Structure-Based Screen Identifies a Potent Small Molecule Inhibitor of Stat5a/b with Therapeutic Potential for Prostate Cancer and Chronic Myeloid Leukemia." (2015). Department of Cancer Biology Faculty Papers. Paper 96.
https://jdc.jefferson.edu/cbfp/96
PubMed ID
26026053
Comments
This article has been peer reviewed. It is the authors' final version prior to publication in Molecular Cancer Therapeutics
Volume 14, Issue 8, August 2015, Pages 1777-1793.
The published version is available at DOI: 10.1158/1535-7163.MCT-14-0883. Copyright © American Association for Cancer Research