A “Ligand First” Approach toward Selective, Covalent JNK2/3 Inhibitors

All JNK isoforms play a specific role in various diseases.
The
role of the JNK2 isoform has so far received little attention compared
to its JNK1 and JNK3 counterparts with JNK3 being a potential target
for neurodegenerative diseases and an inhibitor with JNK1 bias being
currently investigated in clinical trials. Using an iterative, structure-guided
optimization approach starting from a reported reversible binding
aminopyrazole-derived scaffold, novel highly potent JNK2/3 selective
inhibitors were generated (“ligand-first approach”).
These reversible inhibitors were further transformed to covalent inhibitors
by attaching an electrophilic warhead moiety, able to address a conserved
cysteine side chain present in JNKs. Reversible and covalent inhibitors
presented in this study show high JNK2/3 isoform selectivity and activity
in cells. The covalently acting lead compound 56d shows
good kinetic data with a kinact/KI (JNK2) = 38,200 M–1 s–1 as well as cellular isoform selectivity and a clean
kinome profile.