2. Academic Validation
  3. PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor

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

  • Sci Rep. 2020 Sep 28;10(1):15826. doi: 10.1038/s41598-020-72869-9.
Tigist Y Tamir 1,  David H Drewry 2 3,  Carrow Wells 2 3,  M Ben Major 1 4 5,  Alison D Axtman 6 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 2 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 3 Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 4 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
  • 5 Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO, USA.
  • 6 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
  • 7 Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
PMID: 32985588 DOI: 10.1038/s41598-020-72869-9
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.

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