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.