PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor

Abstract The Published Kinase Inhibitor Set (PKIS) is a publicly-available chemogenomic library distributed to more than 300 laboratories by GlaxoSmithKline (GSK) between 2011 and 2015 and by SGC-UNC from 2015 to 2017. Screening this library of well-annotated, published kinase inhibitors has yielded...

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Autores principales:	Tigist Y. Tamir, David H. Drewry, Carrow Wells, M. Ben Major, Alison D. Axtman
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2427271ceabc4a4d9e480023fca08c5f
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spelling	oai:doaj.org-article:2427271ceabc4a4d9e480023fca08c5f2021-12-02T18:51:06ZPKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor10.1038/s41598-020-72869-92045-2322https://doaj.org/article/2427271ceabc4a4d9e480023fca08c5f2020-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-72869-9https://doaj.org/toc/2045-2322Abstract The Published Kinase Inhibitor Set (PKIS) is a publicly-available chemogenomic library distributed to more than 300 laboratories by GlaxoSmithKline (GSK) between 2011 and 2015 and by SGC-UNC from 2015 to 2017. Screening this library of well-annotated, published kinase inhibitors has yielded a plethora of data in diverse therapeutic and scientific areas, funded applications, publications, and provided impactful pre-clinical results. GW296115 is a compound that was included in PKIS based on its promising selectivity following profiling against 260 human kinases. Herein we present more comprehensive profiling data for 403 wild type human kinases and follow-up enzymatic screening results for GW296115. This more thorough investigation of GW296115 has confirmed it as a potent inhibitor of kinases including BRSK1 and BRSK2 that were identified in the original panel of 260 kinases as well as surfaced other kinases that it potently inhibits. Based on these new kinome-wide screening results, we report that GW296115 is an inhibitor of several members of the Illuminating the Druggable Genome (IDG) list of understudied dark kinases. Specifically, our results establish GW296115 as a potent lead chemical tool that inhibits six IDG kinases with IC50 values less than 100 nM. Focused studies establish that GW296115 is cell active, and directly engages BRSK2. Further evaluation showed that GW296115 downregulates BRSK2-driven phosphorylation and downstream signaling. Therefore, we present GW296115 as a cell-active chemical tool that can be used to interrogate the poorly characterized function(s) of BRSK2.Tigist Y. TamirDavid H. DrewryCarrow WellsM. Ben MajorAlison D. AxtmanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-12 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tigist Y. Tamir David H. Drewry Carrow Wells M. Ben Major Alison D. Axtman PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor
description	Abstract The Published Kinase Inhibitor Set (PKIS) is a publicly-available chemogenomic library distributed to more than 300 laboratories by GlaxoSmithKline (GSK) between 2011 and 2015 and by SGC-UNC from 2015 to 2017. Screening this library of well-annotated, published kinase inhibitors has yielded a plethora of data in diverse therapeutic and scientific areas, funded applications, publications, and provided impactful pre-clinical results. GW296115 is a compound that was included in PKIS based on its promising selectivity following profiling against 260 human kinases. Herein we present more comprehensive profiling data for 403 wild type human kinases and follow-up enzymatic screening results for GW296115. This more thorough investigation of GW296115 has confirmed it as a potent inhibitor of kinases including BRSK1 and BRSK2 that were identified in the original panel of 260 kinases as well as surfaced other kinases that it potently inhibits. Based on these new kinome-wide screening results, we report that GW296115 is an inhibitor of several members of the Illuminating the Druggable Genome (IDG) list of understudied dark kinases. Specifically, our results establish GW296115 as a potent lead chemical tool that inhibits six IDG kinases with IC50 values less than 100 nM. Focused studies establish that GW296115 is cell active, and directly engages BRSK2. Further evaluation showed that GW296115 downregulates BRSK2-driven phosphorylation and downstream signaling. Therefore, we present GW296115 as a cell-active chemical tool that can be used to interrogate the poorly characterized function(s) of BRSK2.
format	article
author	Tigist Y. Tamir David H. Drewry Carrow Wells M. Ben Major Alison D. Axtman
author_facet	Tigist Y. Tamir David H. Drewry Carrow Wells M. Ben Major Alison D. Axtman
author_sort	Tigist Y. Tamir
title	PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor
title_short	PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor
title_full	PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor
title_fullStr	PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor
title_full_unstemmed	PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor
title_sort	pkis deep dive yields a chemical starting point for dark kinases and a cell active brsk2 inhibitor
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/2427271ceabc4a4d9e480023fca08c5f
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PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor

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