Short Communication - Stem Cell Research and Regenerative Medicine (2020)

SH2-targeting Stat5 inhibitor IST5-002 has high transcriptomic specificity and low toxicity in vivo

Marja T Nevalainen

The Medical College of Wisconsin, USA


Stat5a/b (Stat5) is critical for growth and progression of solid tumors and hematological malignancies, specifically prostate cancer (PC) and Bcr-Abl–driven leukemias. Also, Stat5 is known to induce cancer stem cell phenotype. For therapeutic suppression, transcription factors are typically considered suboptimal pharmacological targets because their function relies on protein– protein and protein–DNA interactions that are not easily disrupted by small molecules. Targeting Stat5, however, offers a unique opportunity for development of pharmacological inhibitors because Stat5 serves both as a cytoplasmic signaling molecule and a nuclear transcription factor and can be suppressed when located in cytoplasm as a signaling protein. Using in silico screening, combined with medicinal chemistry, we developed a lead compound Stat5a/b inhibitor, IST5-002 (IST5). In order to evaluate the potential of IST5 for additional lead optimization for clinical development, we evaluated the transcriptomic specificity of IST5 vs. genetic knockdown of Stat5 in cells. In addition, we further evaluated the efficacy and the mechanism of action of IST5 in blocking the Jak2-Stat5 signaling cascade. Finally, we investigated the acute, sub-chronic and chronic toxicity profiles of IST5 in vivo in mice. Our results show that the SH2-domain targeting IST5 has high transcriptional specificity in PC cells. IST5 has minimal specific inhibitory activity against 54 typical kinases in cancer cells. Using two different assays of Stat5-dimerization, we demonstrate high efficacy of IST5 in suppressing dimerization step of Stat5 activation and that the phosphate group of IST5, which increases its transfer across the cell membrane, is not critical for its activity in cellbased assays. Finally, IST5 did not causeany significant acute, subchronic or chronic toxic effects or changes in the blood profiles in mice. In summary, the present work supports lead optimization of the Stat5 inhibitor IST5 towards clinical development for therapies for solid tumors, hematological malignancies and myeloproliferative disorders.


Marja T Nevalainen is an internationally recognized leader in the field of cytokine and steroid hormone signaling in prostate cancer. The focus of her laboratory is on translational research on prostate cancer and pancreatic cancer to develop and improve diagnostics and develop new therapies. She holds the title of Eminent Scholar at MCW. She is also Director of Prostate Cancer Center of Excellence at MCW Cancer Center, which is a multidisciplinary hub for prostate cancer research within the institution with an international collaborative network. She also serves as Assistant Dean for Research at MCW, and Associate Director of Education for the MCW Cancer Center. Her primary appointment is in the Department of Pathology and a secondary appointment in the Department of Pharmacology and Toxicolog


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■ Enzalutamide-Induced Feed-Forward Signaling Loop Promotes TherapyResistant Prostate Cancer Growth Providing an Exploitable Molecular Target for Jak2 Inhibitors. (Udhane V, Maranto C, Hoang DT, Gu L, Erickson A, Devi S, Talati PG, Banerjee A, Iczkowski KA, Jacobsohn K, See WA, Mirtti T, Kilari D, Nevalainen MT.) Mol Cancer Ther. 2020 01;19(1):231-246 PMID: 31548294 PMCID: PMC6946850

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