Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein

[Image: see text] 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 v...

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Autores principales: Cumaraswamy, Abbarna A., Lewis, Andrew M., Geletu, Mulu, Todic, Aleksandra, Diaz, Diego B., Cheng, Xin Ran, Brown, Carla E., Laister, Rob C., Muench, David, Kerman, Kagan, Grimes, H. Leighton, Minden, Mark D., Gunning, Patrick T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234445/
https://www.ncbi.nlm.nih.gov/pubmed/25419444
http://dx.doi.org/10.1021/ml500165r
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author Cumaraswamy, Abbarna A.
Lewis, Andrew M.
Geletu, Mulu
Todic, Aleksandra
Diaz, Diego B.
Cheng, Xin Ran
Brown, Carla E.
Laister, Rob C.
Muench, David
Kerman, Kagan
Grimes, H. Leighton
Minden, Mark D.
Gunning, Patrick T.
author_facet Cumaraswamy, Abbarna A.
Lewis, Andrew M.
Geletu, Mulu
Todic, Aleksandra
Diaz, Diego B.
Cheng, Xin Ran
Brown, Carla E.
Laister, Rob C.
Muench, David
Kerman, Kagan
Grimes, H. Leighton
Minden, Mark D.
Gunning, Patrick T.
author_sort Cumaraswamy, Abbarna A.
collection PubMed
description [Image: see text] 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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spelling pubmed-42344452015-09-19 Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein Cumaraswamy, Abbarna A. Lewis, Andrew M. Geletu, Mulu Todic, Aleksandra Diaz, Diego B. Cheng, Xin Ran Brown, Carla E. Laister, Rob C. Muench, David Kerman, Kagan Grimes, H. Leighton Minden, Mark D. Gunning, Patrick T. ACS Med Chem Lett [Image: see text] 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. American Chemical Society 2014-09-19 /pmc/articles/PMC4234445/ /pubmed/25419444 http://dx.doi.org/10.1021/ml500165r Text en Copyright © 2014 American Chemical Society
spellingShingle Cumaraswamy, Abbarna A.
Lewis, Andrew M.
Geletu, Mulu
Todic, Aleksandra
Diaz, Diego B.
Cheng, Xin Ran
Brown, Carla E.
Laister, Rob C.
Muench, David
Kerman, Kagan
Grimes, H. Leighton
Minden, Mark D.
Gunning, Patrick T.
Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein
title Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein
title_full Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein
title_fullStr Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein
title_full_unstemmed Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein
title_short Nanomolar-Potency Small Molecule Inhibitor of STAT5 Protein
title_sort nanomolar-potency small molecule inhibitor of stat5 protein
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234445/
https://www.ncbi.nlm.nih.gov/pubmed/25419444
http://dx.doi.org/10.1021/ml500165r
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