Inhibitors Targeting STAT5 Signaling in Myeloid Leukemias: New Tetrahydroquinoline Derivatives with Improved Antileukemic Potential

Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are two closely related STAT family members that are crucial downstream effectors of tyrosine kinase oncoproteins such as FLT3-ITD in acute myeloid leukemia (AML) and BCR-ABL in chronic myeloid leukemia (CML). We recently developed and reported the synthesis of a first molecule called 17f that selectively inhibits STAT5 signaling in myeloid leukemia cells and overcomes their resistance to chemotherapeutic agents. To improve the antileukemic effect of 17f , we synthesized 10 analogs of this molecule and analyzed their impact on cell growth, survival, chemoresistance and STAT5 signaling. Two compounds, 7a and 7a' , were identified as having similar or higher antileukemic effects in various AML and CML cell lines. Both molecules were found to be more effective than 17f to inhibit STAT5 activity/expression and to suppress the chemoresistance of CML.