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.
Highlights
There is an unmet medical need for pharmacologic inhibitors of signal transducer and activator of transcription 5a/b (Stat5a/b)
Cells were treated with IST5-002 or Ctrl for 2 hours prior to and during Stat5a/b activation by stimulation with human prolactin
A critical role of Stat5a/b in pathogenesis of prostate cancer and myeloproliferative disorders has been established [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22, 24], only a few pharmacologic Stat5a/b inhibitors are currently available for clinical development [15, 42,43,44]
Summary
There is an unmet medical need for pharmacologic inhibitors of signal transducer and activator of transcription 5a/b (Stat5a/b). Multiple findings support Stat5a/b as a therapeutic target protein in prostate cancer: (i) inhibition of Stat5a/b expression or activation induces rapid apoptotic prostate cancer cell death [1,2,3, 9, 22]; (ii) blockade of Stat5a/b signaling inhibits growth of both primary prostate cancer and CRPC [2, 4, 5, 9, 21,22,23]; (iii) Stat5a/b promotes epithelial–mesenchymal transition (EMT) and metastasis of human prostate cancer [5]; (iv) the Stat5a/b gene locus is frequently amplified in clinical prostate cancers during progression to metastatic CRPC [6]; (v) Stat5a/b activation in prostate cancer predicts early recurrence and prostate cancer–specific death [7, 8, 21].
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