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Nanomolar-potency small molecule inhibitor of STAT5 protein

Cumaraswamy, AA and Lewis, AM and Geletu, M and Todic, A and Diaz, DB and Cheng, XR and Brown, CE and Laister, RC and Muench, D and Kerman, K and Grimes, HL and Minden, MD and Gunning, PT (2014) Nanomolar-potency small molecule inhibitor of STAT5 protein. ACS Medicinal Chemistry Letters, 5 (11). pp. 1202-1206. ISSN 1948-5875

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Abstract

© 2014 American Chemical Society. 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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