%0 Journal Article
%A Wydra, Valentin R
%A Plank, Nicole
%A Zwirner, Stefan
%A Selig, Roland
%A Rasch, Alexander
%A Masberg, Benedikt
%A Lämmerhofer, Michael
%A Zender, Lars
%A Koch, Pierre
%A Albrecht, Wolfgang
%A Laufer, Stefan
%T A 'Ligand First' Approach toward Selective, Covalent JNK2/3 Inhibitors.
%J Journal of medicinal chemistry
%V 68
%N 11
%@ 0095-9065
%C Washington, DC
%I ACS
%M DKFZ-2025-01060
%P 12004-12028
%D 2025
%Z 2025 Jun 12;68(11):12004-12028
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40404564
%R 10.1021/acs.jmedchem.5c00884
%U https://inrepo02.dkfz.de/record/301539