Design and Development of a Chemical Probe for Pseudokinase Ca 2+/calmodulin-Dependent Ser/Thr Kinase

J Med Chem. 2021 Oct 14;64(19):14358-14376. doi: 10.1021/acs.jmedchem.1c00845. Epub 2021 Sep 20.

Abstract

CASK (Ca2+/calmodulin-dependent Ser/Thr kinase) is a member of the MAGUK (membrane-associated guanylate kinase) family that functions as neurexin kinases with roles implicated in neuronal synapses and trafficking. The lack of a canonical DFG motif, which is altered to GFG in CASK, led to the classification as a pseudokinase. However, functional studies revealed that CASK can still phosphorylate substrates in the absence of divalent metals. CASK dysfunction has been linked to many diseases, including colorectal cancer, Parkinson's disease, and X-linked mental retardation, suggesting CASK as a potential drug target. Here, we exploited structure-based design for the development of highly potent and selective CASK inhibitors based on 2,4-diaminopyrimidine-5-carboxamides targeting an unusual pocket created by the GFG motif. The presented inhibitor design offers a more general strategy for the development of pseudokinase ligands that harbor unusual sequence motifs. It also provides a first chemical probe for studying the biological roles of CASK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium-Calmodulin-Dependent Protein Kinases / chemistry
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Drug Design
  • Humans
  • Molecular Probes / chemistry*
  • Molecular Probes / pharmacology
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology
  • Serine / chemistry*
  • Structure-Activity Relationship
  • Substrate Specificity
  • Threonine / chemistry*

Substances

  • Molecular Probes
  • Protein Kinase Inhibitors
  • Threonine
  • Serine
  • Calcium-Calmodulin-Dependent Protein Kinases