Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein | Zendy

Abbarna A. Cumaraswamy | Zendy; Andrew M. Lewis | Zendy; Mulu Geletu | Zendy; Aleksandra Todic | Zendy; Diego B. Diaz | Zendy; Xin R. Cheng | Zendy; Carla E. Brown | Zendy; Rob C. Laister | Zendy; David E. Muench | Zendy; Kağan Kerman | Zendy; H. Leighton Grimes | Zendy; Mark D. Minden | Zendy; Patrick T. Gunning | Zendy

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Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein

Author(s) -

Abbarna A. Cumaraswamy,

Andrew M. Lewis,

Mulu Geletu,

Aleksandra Todic,

Diego B. Diaz,

Xin R. Cheng,

Carla E. Brown,

Rob C. Laister,

David E. Muench,

Kağan Kerman,

H. Leighton Grimes,

Mark D. Minden,

Patrick T. Gunning

Publication year - 2014

Publication title -

acs medicinal chemistry letters

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.065

H-Index - 66

ISSN - 1948-5875

DOI - 10.1021/ml500165r

Subject(s) - stat5 , small molecule , mcl1 , chemistry , in vitro , cancer research , biochemistry , microbiology and biotechnology , computational biology , biology , phosphorylation , downregulation and upregulation , gene

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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