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, Costas D Lallas, Shilpa Gupta, Elyse Ellsworth, Shauna Blackmon, Adam Ertel, Paolo Fortina, Benjamin Leiby, Guanjun Xia, Hallgeir Rui, David T HoangLeonard G Gomella, Gino Cingolani, Vincent Njar, Nagarajan Pattabiraman, Bruno Calabretta, Marja T Nevalainen

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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 (PC) 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 (PC) 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 1.5 μM) and Stat5b (IC50 3.5 μM). IST5-002 suppressed nuclear translocation of Stat5a/b, binding to DNA and Stat5a/b target gene expression. IST5-002 induced extensive apoptosis of PC cells, impaired growth of PC xenograft tumors and induced cell death in patient-derived PCs when tested ex vivo in explant organ cultures. Importantly, IST5-002 induced robust apoptotic death not only of imatinib-sensitive but also imatinib-resistant chronic myeloid leukemia (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 hematological malignancies.

Original languageEnglish
JournalMolecular Cancer Therapeutics
Publication statusPublished - 29 May 2015


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