SGC-GAK-1: A Chemical Probe for Cyclin G Associated Kinase (GAK)

  • J Med Chem. 2019 Mar 14;62(5):2830-2836. doi: 10.1021/acs.jmedchem.8b01213.
Christopher R M Asquith ,  Benedict-Tilman Berger  1  2 ,  Jing Wan ,  James M Bennett  3 ,  Stephen J Capuzzi ,  Daniel J Crona ,  David H Drewry ,  Michael P East ,  Jonathan M Elkins  3  4 ,  Oleg Fedorov  3 ,  Paulo H Godoi  4 ,  Debra M Hunter ,  Stefan Knapp  1  2 ,  Susanne Müller  1 ,  Chad D Torrice ,  Carrow I Wells ,  H Shelton Earp ,  Timothy M Willson ,  William J Zuercher
Affiliations
  • 1. Structural Genomics Consortium, Johann Wolfgang Goethe University, Buchmann Institute for Molecular Life Sciences, Max-von-Laue-Straße 15 , D-60438 Frankfurt am Main , Germany.
  • 2. Institute for Pharmaceutical Chemistry , Johann Wolfgang Goethe University , Max-von-Laue-Straße 9 , D-60438 Frankfurt am Main , Germany.
  • 3. Structural Genomics Consortium and Target Discovery Institute, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building , Oxford OX3 7DQ , U.K.
  • 4. Structural Genomics Consortium , Universidade Estadual de Campinas , Campinas , São Paulo 13083-886 , Brazil.
PMID: 30768268 DOI: 10.1021/acs.jmedchem.8b01213
Abstract

We describe SGC-GAK-1 (11), a potent, selective, and cell-active inhibitor of cyclin G-associated kinase (GAK), together with a structurally related negative control SGC-GAK-1N (14). 11 was highly selective in an in vitro kinome-wide screen, but cellular engagement assays defined RIPK2 as a collateral target. We identified 18 as a potent RIPK2 Inhibitor lacking GAK activity. Together, this chemical probe set can be used to interrogate GAK cellular biology.

Products