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Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein
Abbarna A Cumaraswamy1, Andrew M Lewis1, Mulu Geletu1
1Department of Chemistry, University of Toronto Mississauga , Mississauga, Ontario L5L 1C6, Canada.
Abstract:
We herein report the design and synthesis of the first nanomolar binding inhibitor of STAT5 protein. Lead compound 13a, possessing a phosphotyrosyl-mimicking salicylic acid group, potently and selectively binds to STAT5 over STAT3, inhibits STAT5-SH2 domain complexation events in vitro, silences activated STAT5 in leukemic cells, as well as STAT5's downstream transcriptional targets, including MYC and MCL1, and, as a result, leads to apoptosis. We believe 13a represents a useful probe for interrogating STAT5 function in cells as well as being a potential candidate for advanced preclinical trials.
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