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Prospects for Clinical Development of Stat5 Inhibitor IST5-002: High Transcriptomic Specificity in Prostate Cancer and Low Toxicity In Vivo. Cancers (Basel) 2020 Nov 18;12(11)

Date

11/22/2020

Pubmed ID

33217941

Pubmed Central ID

PMC7724566

DOI

10.3390/cancers12113412

Scopus ID

2-s2.0-85096199725   1 Citation

Abstract

Stat5 is of significant interest in the search for new therapeutics for prostate cancer (PC) and hematopoietic disorders. We evaluated the transcriptomic specificity of the Stat5a/b inhibitor IST5-002 (IST5) in PC, defined more closely its mechanisms of action, and investigated the in vivo toxicity of IST5 for further optimization for clinical development. The transcriptomic specificity of IST5 vs. genetic Stat5 knockdown was evaluated by RNA-seq analysis, which showed high similarity with the Pearson correlation coefficient ranging from 0.98-0.99. The potency of IST5 vs. its derivative lacking the phosphate group in suppressing Stat5 was evaluated in two separate but complementary assays. The inhibitory activity of IST5 against kinases was investigated in cell-free assays followed by more focused evaluation in a cell-based assay. IST5 has no specific inhibitory activity against 54 kinases, while suppressing Stat5 phosphorylation and subsequent dimerization in PC cells. The phosphate group was not critical for the biological activity of IST5 in cells. The acute, sub-chronic and chronic toxicity studies of IST5 were carried out in mice. IST5 did not cause any significant toxic effects or changes in the blood profiles. The present work supports further optimization of IST5 for oral bioavailability for clinical development for therapies for solid tumors, hematological and myeloproliferative disorders.

Author List

Maranto C, Udhane V, Jia J, Verma R, M??ller-Newen G, LaViolette PS, Pereckas M, Sabharwal L, Terhune S, Pattabiraman N, Njar VCO, Imig JD, Wang L, Nevalainen MT

Authors

John D. Imig PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Peter LaViolette PhD Associate Professor in the Radiology department at Medical College of Wisconsin
Marja T. Nevalainen MD, PhD Assistant Dean, Professor in the Pathology department at Medical College of Wisconsin
Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin