TY  - JOUR
AU  - Wydra, Valentin R
AU  - Plank, Nicole
AU  - Zwirner, Stefan
AU  - Selig, Roland
AU  - Rasch, Alexander
AU  - Masberg, Benedikt
AU  - Lämmerhofer, Michael
AU  - Zender, Lars
AU  - Koch, Pierre
AU  - Albrecht, Wolfgang
AU  - Laufer, Stefan
TI  - A 'Ligand First' Approach toward Selective, Covalent JNK2/3 Inhibitors.
JO  - Journal of medicinal chemistry
VL  - 68
IS  - 11
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - DKFZ-2025-01060
SP  - 12004-12028
PY  - 2025
N1  - 2025 Jun 12;68(11):12004-12028
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40404564
DO  - DOI:10.1021/acs.jmedchem.5c00884
UR  - https://inrepo02.dkfz.de/record/301539
ER  -