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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.

Original publication

DOI

10.1021/ml500165r

Type

Journal article

Journal

ACS Med Chem Lett

Publication Date

13/11/2014

Volume

5

Pages

1202 - 1206

Keywords

STAT5, anticancer drug, leukemia cells, protein−protein interactions, small-molecule inhibitor