Prospects for Clinical Development of Stat5 Inhibitor IST5-002: High Transcriptomic Specificity in Prostate Cancer and Low Toxicity In Vivo

Cristina Maranto; Vindhya Udhane; Jing Jia; Ranjit Verma; Gerhard Müller-Newen; Peter S LaViolette; Michael Pereckas; Lavannya Sabharwal; Scott Terhune; Nagarajan Pattabiraman; Vincent C O Njar; John D Imig; Liang Wang; Marja T Nevalainen

doi:10.3390/cancers12113412

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):3412. doi: 10.3390/cancers12113412.

Authors

Cristina Maranto^{1

2

3}, Vindhya Udhane^{1

2

3}, Jing Jia⁴, Ranjit Verma², Gerhard Müller-Newen⁵, Peter S LaViolette^{6

3}, Michael Pereckas⁷, Lavannya Sabharwal^{1

2

3}, Scott Terhune⁸, Nagarajan Pattabiraman⁹, Vincent C O Njar¹⁰, John D Imig², Liang Wang⁴, Marja T Nevalainen^{1

2

3}

Affiliations

¹ Department of Pathology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
² Department of Pharmacology and Toxicology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
³ Prostate Cancer Center of Excellence at Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁴ Department of Tumor Biology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
⁵ Institute of Biochemistry and Molecular Biology, Aachen University, 52066 Aachen, Germany.
⁶ Department of Radiology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁷ Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁸ Department of Microbiology and Immunology, and Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁹ MolBox LLC, Silver Spring, MD 20910, USA.
¹⁰ Department of Pharmacology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA.

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.

Keywords: IST5-002; Stat5; cell signaling; prostate cancer; small-molecule inhibitors; toxicity; transcriptome.

Abstract

Grants and funding