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Development of Organometallic S6K1 Inhibitors

[Image: see text] Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically i...

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Autores principales: Qin, Jie, Rajaratnam, Rajathees, Feng, Li, Salami, Jemilat, Barber-Rotenberg, Julie S., Domsic, John, Reyes-Uribe, Patricia, Liu, Haiying, Dang, Weiwei, Berger, Shelley L., Villanueva, Jessie, Meggers, Eric, Marmorstein, Ronen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289024/
https://www.ncbi.nlm.nih.gov/pubmed/25356520
http://dx.doi.org/10.1021/jm5011868
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author Qin, Jie
Rajaratnam, Rajathees
Feng, Li
Salami, Jemilat
Barber-Rotenberg, Julie S.
Domsic, John
Reyes-Uribe, Patricia
Liu, Haiying
Dang, Weiwei
Berger, Shelley L.
Villanueva, Jessie
Meggers, Eric
Marmorstein, Ronen
author_facet Qin, Jie
Rajaratnam, Rajathees
Feng, Li
Salami, Jemilat
Barber-Rotenberg, Julie S.
Domsic, John
Reyes-Uribe, Patricia
Liu, Haiying
Dang, Weiwei
Berger, Shelley L.
Villanueva, Jessie
Meggers, Eric
Marmorstein, Ronen
author_sort Qin, Jie
collection PubMed
description [Image: see text] Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previously used to target other kinases. Biochemical data demonstrate that EM5 and FL772 inhibit the kinase with IC(50) value in the low nanomolar range at 100 μM ATP and that the more potent FL772 compound has a greater than 100-fold specificity over S6K2. The crystal structures of S6K1 bound to staurosporine, EM5, and FL772 reveal that the EM5 and FL772 inhibitors bind in the ATP binding pocket and make S6K1-specific contacts, resulting in changes to the p-loop, αC helix, and αD helix when compared to the staurosporine-bound structure. Cellular data reveal that FL772 is able to inhibit S6K phosphorylation in yeast cells. Together, these studies demonstrate that potent, selective, and cell permeable S6K1 inhibitors can be prepared and provide a scaffold for future development of S6K inhibitors with possible therapeutic applications.
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spelling pubmed-42890242015-01-10 Development of Organometallic S6K1 Inhibitors Qin, Jie Rajaratnam, Rajathees Feng, Li Salami, Jemilat Barber-Rotenberg, Julie S. Domsic, John Reyes-Uribe, Patricia Liu, Haiying Dang, Weiwei Berger, Shelley L. Villanueva, Jessie Meggers, Eric Marmorstein, Ronen J Med Chem [Image: see text] Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previously used to target other kinases. Biochemical data demonstrate that EM5 and FL772 inhibit the kinase with IC(50) value in the low nanomolar range at 100 μM ATP and that the more potent FL772 compound has a greater than 100-fold specificity over S6K2. The crystal structures of S6K1 bound to staurosporine, EM5, and FL772 reveal that the EM5 and FL772 inhibitors bind in the ATP binding pocket and make S6K1-specific contacts, resulting in changes to the p-loop, αC helix, and αD helix when compared to the staurosporine-bound structure. Cellular data reveal that FL772 is able to inhibit S6K phosphorylation in yeast cells. Together, these studies demonstrate that potent, selective, and cell permeable S6K1 inhibitors can be prepared and provide a scaffold for future development of S6K inhibitors with possible therapeutic applications. American Chemical Society 2014-10-30 2015-01-08 /pmc/articles/PMC4289024/ /pubmed/25356520 http://dx.doi.org/10.1021/jm5011868 Text en Copyright © 2014 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Qin, Jie
Rajaratnam, Rajathees
Feng, Li
Salami, Jemilat
Barber-Rotenberg, Julie S.
Domsic, John
Reyes-Uribe, Patricia
Liu, Haiying
Dang, Weiwei
Berger, Shelley L.
Villanueva, Jessie
Meggers, Eric
Marmorstein, Ronen
Development of Organometallic S6K1 Inhibitors
title Development of Organometallic S6K1 Inhibitors
title_full Development of Organometallic S6K1 Inhibitors
title_fullStr Development of Organometallic S6K1 Inhibitors
title_full_unstemmed Development of Organometallic S6K1 Inhibitors
title_short Development of Organometallic S6K1 Inhibitors
title_sort development of organometallic s6k1 inhibitors
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289024/
https://www.ncbi.nlm.nih.gov/pubmed/25356520
http://dx.doi.org/10.1021/jm5011868
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