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Polomski, Marion; Brachet‐Botineau, Marie; Juen, Ludovic; Viaud‐Massuard, Marie‐Claude; Gouilleux, Fabrice; Prié, Gildas
ChemMedChem, March 18, 2021, Letnik: 16, Številka: 6Journal Article
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 17 f that selectively inhibits STAT5 signaling in myeloid leukemia cells and overcomes their resistance to chemotherapeutic agents. To improve the antileukemic effect of 17 f, we synthesized ten analogs of this molecule and analyzed their impact on cell growth, survival, chemoresistance and STAT5 signaling. Two compounds, 7 a and 7 a’, 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 17 f at inhibiting STAT5 activity/expression and suppressing the chemoresistance of CML. Lead on: To improve the antileukemic activity of lead compound, 17 f, new derivatives were synthesized by pharmacomodulation. Two compounds, 7 a and 7 a’, showed similar or higher antileukemic effects in various acute and chronic myeloid leukemias cell lines. Both compounds were found to be more effective than 17 f in inhibiting STAT5 activity/expression and suppressing the chemoresistance of CML cells.
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