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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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A "Ligand First" Approach toward Selective, Covalent JNK2/3 Inhibitors
Valentin R Wydra1, Nicole Plank2, Stefan Zwirner3
1Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, DE, Germany.
None:
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.
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