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

Mol Cancer Ther. 2015 Aug;14(8):1777-93. doi: 10.1158/1535-7163.MCT-14-0883.

Zhiyong Liao ¹, Lei Gu ¹, Jenny Vergalli ¹, Samanta A Mariani ¹, Marco De Dominici ¹, Ravi K Lokareddy ², Ayush Dagvadorj ¹, Puranik Purushottamachar ³, Peter A McCue ⁴, Edouard Trabulsi ⁵, Costas D Lallas ⁵, Shilpa Gupta ⁶, Elyse Ellsworth ¹, Shauna Blackmon ¹, Adam Ertel ¹, Paolo Fortina ¹, Benjamin Leiby ⁷, Guanjun Xia ¹, Hallgeir Rui ⁸, David T Hoang ¹, Leonard G Gomella ⁵, Gino Cingolani ², Vincent Njar ³, Nagarajan Pattabiraman ⁹, Bruno Calabretta ¹, Marja T Nevalainen ¹⁰

Affiliations

1 Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
2 Department of Biochemistry, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
3 School of Pharmacy, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
4 Department of Pathology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
5 Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
6 Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
7 Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
8 Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Pathology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
9 Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
10 Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. mnevalainen@mcw.edu.

PMID: 26026053 DOI: 10.1158/1535-7163.MCT-14-0883

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-19527

IST5-002

99.36%, Stat5a/b Inhibitor

STAT; Apoptosis

Cancer

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