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.