Wydra, Valentin R. and Plank, Nicole and Zwirner, Stefan and Selig, Roland and Rasch, Alexander and Masberg, Benedikt and Laemmerhofer, Michael and Zender, Lars and Koch, Pierre and Albrecht, Wolfgang and Laufer, Stefan (2025) A "Ligand First" Approach toward Selective, Covalent JNK2/3 Inhibitors. JOURNAL OF MEDICINAL CHEMISTRY, 68 (11). pp. 12004-12028. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)Abstract
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 k inact/K I (JNK2) = 38,200 M-1 s-1 as well as cellular isoform selectivity and a clean kinome profile.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PROTEIN-KINASE; JNK3; POTENT; DISCOVERY; DESIGN; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Apr 2026 08:55 |
| Last Modified: | 17 Apr 2026 08:55 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67724 |
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