Abstract
Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic cancers. STAT3 and STAT5 are common targets for different tyrosine kinase oncogenes (TKOs). In addition, STAT3 and STAT5 proteins were shown to contain activating mutations in some rare but aggressive leukemias/lymphomas. Both proteins also contribute to drug resistance in hematopoietic malignancies and are now well recognized as major targets in cancer treatment. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations during the last decade. This review summarizes the current knowledge of oncogenic STAT3 and STAT5 functions in hematopoietic cancers as well as advances in preclinical and clinical development of pharmacological inhibitors.
Highlights
Signal Transducer and Activator of Transcription (STAT) proteins are a seven-member family of cytoplasmic transcription factors that relay signals emanating from cell-surface cytokine and growth factor receptors to the nucleus [1,2]
Computer simulations and other in silico studies such as high-throughput virtual screening, cell-based assays, biophysical and biochemical approaches led to the identification of selective STAT3/5 inhibitors with potent anticancer effects
STAT3/5 inhibitors are likely to become a valuable addition to the expanding arsenal of drugs against hematopoietic cancers and solid tumors
Summary
Modalities for targeting STAT3 and STAT5 in hematologic cancers can be classified into direct and indirect approaches. Compounds directly targeting STAT3 or STAT5 canonical functions may either inhibit dimerization, DNA binding, or transcriptional activity. Indirect approaches include preventing ligands binding to growth factor or cytokine receptors, inhibiting upstream tyrosine kinases such as TKOs, targeting the nucleocytoplasmic shuttling of STAT3/5, or activating negative regulators of STAT3/5 such as the tyrosine phosphatases SOCS or PIAS [189,190,191]. Both direct or indirect approaches might be applied to non-canonical functions. We will discuss the limitations of STAT3/5 inhibitors in the treatment of these diseases and promising outcomes when combined with other pharmacological compounds
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