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.

Structure-based screen identifies a potent small molecule inhibitor of Stat5a/b with therapeutic potential for prostate cancer and chronic myeloid leukemia / Liao, Zhiyong; Gu, Lei; Vergalli, Jenny; Mariani, Samanta A.; De Dominici, Marco; Lokareddy, Ravi K.; Dagvadorj, Ayush; Purushottamachar, Puranik; Mccue, Peter A.; Trabulsi, Edouard; Lallas, Costas D.; Gupta, Shilpa; Ellsworth, Elyse; Blackmon, Shauna; Ertel, Adam; Fortina, Paolo; Leiby, Benjamin; Xia, Guanjun; Rui, Hallgeir; Hoang, David T.; Gomella, Leonard G.; Cingolani, Gino; Njar, Vincent; Pattabiraman, Nagarajan; Calabretta, Bruno; Nevalainen, Marja T.. - In: MOLECULAR CANCER THERAPEUTICS. - ISSN 1535-7163. - 14:8(2015), pp. 1777-1793. [10.1158/1535-7163.MCT-14-0883]

Structure-based screen identifies a potent small molecule inhibitor of Stat5a/b with therapeutic potential for prostate cancer and chronic myeloid leukemia

CALABRETTA, Bruno;
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.
29-mag-2015
14
8
1777
1793
Structure-based screen identifies a potent small molecule inhibitor of Stat5a/b with therapeutic potential for prostate cancer and chronic myeloid leukemia / Liao, Zhiyong; Gu, Lei; Vergalli, Jenny; Mariani, Samanta A.; De Dominici, Marco; Lokareddy, Ravi K.; Dagvadorj, Ayush; Purushottamachar, Puranik; Mccue, Peter A.; Trabulsi, Edouard; Lallas, Costas D.; Gupta, Shilpa; Ellsworth, Elyse; Blackmon, Shauna; Ertel, Adam; Fortina, Paolo; Leiby, Benjamin; Xia, Guanjun; Rui, Hallgeir; Hoang, David T.; Gomella, Leonard G.; Cingolani, Gino; Njar, Vincent; Pattabiraman, Nagarajan; Calabretta, Bruno; Nevalainen, Marja T.. - In: MOLECULAR CANCER THERAPEUTICS. - ISSN 1535-7163. - 14:8(2015), pp. 1777-1793. [10.1158/1535-7163.MCT-14-0883]
Liao, Zhiyong; Gu, Lei; Vergalli, Jenny; Mariani, Samanta A.; De Dominici, Marco; Lokareddy, Ravi K.; Dagvadorj, Ayush; Purushottamachar, Puranik; Mccue, Peter A.; Trabulsi, Edouard; Lallas, Costas D.; Gupta, Shilpa; Ellsworth, Elyse; Blackmon, Shauna; Ertel, Adam; Fortina, Paolo; Leiby, Benjamin; Xia, Guanjun; Rui, Hallgeir; Hoang, David T.; Gomella, Leonard G.; Cingolani, Gino; Njar, Vincent; Pattabiraman, Nagarajan; Calabretta, Bruno; Nevalainen, Marja T.
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