STAT5 transcription factors gain increasing attention as essential drivers in the development of myeloproliferative and lymphoid diseases. STAT5 is often hyper-activated due to deregulated upstream kinase signaling. Additionally, recurrent gain-of-function mutations in the SH2 domain of STAT5 were described, implying its importance in oncogenic transformation independent of driver kinase mutations. To date, various tyrosine kinase inhibitors (TKI) are in the clinics or in clinical trials. However, TKI treatment is often accompanied by resistance development, cytotoxicity as a result of poor kinase selectivity, as well as cardiovascular toxicity. Hence, considering the role of STAT5 in hematopoietic cancers, it is reasonable to directly target STAT5 as a transcriptional regulator.
To inhibit STAT5, we used a small inhibitory molecule (compound X) binding to the SH2 domain of the protein, subsequently resulting in the disruption of STAT5-phosphopeptide interactions. We tested the efficacy of X in STAT5 driven AML/CML cell lines and patient samples. The inhibitor efficiently suppressed transcriptional activity of STAT5, kinase-mediated phosphorylation, dimerization, nuclear translocation, DNA binding and STAT5-mediated gene expression. Importantly, we detected down regulation of c-MYC, Cyclin D1, Cyclin D2, and MCL-oncoproteins, which are important inhibitors of apoptosis and regulators of the cell cycle. Furthermore, X induced extensive apoptosis in MPN cell lines as well as robust apoptotic cell death in patient-derived cells.
Our findings indicate that X is a potent and selective inhibitor of STAT5 and provides a lead structure for further chemical modifications for clinical development to improve existing therapies in MPNs.
