Abstract
The c-Jun N-terminal kinases (JNKs) are evolutionary highly conserved serine/threonine kinases. Numerous findings suggest that JNK3 is involved in the pathogenesis of neurodegenerative diseases, so the inhibition of JNK3 may be a potential therapeutic intervention. The identification of novel compounds with promising pharmacological properties still represents a challenge. Fluorescence thermal shift screening of a chemically diversified lead-like scaffold library of 2024 pure compounds led to the initial identification of seven JNK3 binding hits, which were classified into four scaffold groups according to their chemical structures. Native mass spectrometry validated the interaction of 4 out of the 7 hits with JNK3. Binding geometries and interactions of the top 2 hits were evaluated by docking into a JNK3 crystal structure. Hit 5 had a K d of 21 μM with JNK3 suggested scaffold 5-(phenylamino)-1H-1,2,3-triazole-4-carboxamide as a novel and selective JNK3 binder.