Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein.
Cumaraswamy AA., Lewis AM., Geletu M., Todic A., Diaz DB., Cheng XR., Brown CE., Laister RC., Muench D., Kerman K., Grimes HL., Minden MD., Gunning PT.
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.