2. Academic Validation
  3. Design and Development of a Chemical Probe for Pseudokinase Ca2+/calmodulin-Dependent Ser/Thr Kinase

Design and Development of a Chemical Probe for Pseudokinase Ca2+/calmodulin-Dependent Ser/Thr Kinase

  • J Med Chem. 2021 Oct 14;64(19):14358-14376. doi: 10.1021/acs.jmedchem.1c00845.
Nadine Russ 1 2,  Martin Schröder 1 2,  Benedict-Tilman Berger 1 2,  Sebastian Mandel 1 2,  Yagmur Aydogan 1 2,  Sandy Mauer 3,  Christian Pohl 3,  David H Drewry 4 5,  Apirat Chaikuad 1 2,  Susanne Müller 1 2,  Stefan Knapp 1 2 6
Affiliations

Affiliations

  • 1 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences (BMLS), Goethe University Frankfurt am Main, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany.
  • 2 Institut für Pharmazeutische Chemie, Goethe University Frankfurt am Main, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.
  • 3 Buchman Institute for Molecular Life Science and Institute of Biochemistry II, Goethe University Frankfurt am Main, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany.
  • 4 Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 5 UNC Lineberger Comprehensive Cancer Center, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 6 German Cancer Network (DKTK) and Frankfurt Cancer Institute (FCI), Goethe University Frankfurt am Main, Frankfurt am Main 60438, Germany.
PMID: 34543009 DOI: 10.1021/acs.jmedchem.1c00845
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.

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