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

  • J Med Chem. 2025 Jun 12;68(11):12004-12028. doi: 10.1021/acs.jmedchem.5c00884.
Valentin R Wydra  1 ,  Nicole Plank  2 ,  Stefan Zwirner  3 ,  Roland Selig  1  4 ,  Alexander Rasch  1 ,  Benedikt Masberg  5 ,  Michael Lämmerhofer  5 ,  Lars Zender  3  4  6  7  8 ,  Pierre Koch  2 ,  Wolfgang Albrecht  4 ,  Stefan Laufer  1  6  7  8
Affiliations
  • 1. Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, DE, Germany.
  • 2. Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Universitätsstraße 31, 93053 Regensburg, Germany.
  • 3. Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital of Tübingen, Otfried-Müller-Straße 14, 72076 Tübingen, Germany.
  • 4. HepaRegenix GmbH, Eisenbahnstraße 63, 72072 Tübingen, Germany.
  • 5. Pharmaceutical (Bio-) Analysis, Institute of Pharmaceutical Sciences, Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls Universität Tübingen, Tübingen 72076, Germany.
  • 6. IFIT Cluster of Excellence EXC 2180 'Image Guided and Functionally Instructed Tumor Therapies', Eberhard Karls University of Tübingen, 72076 Tübingen, Germany.
  • 7. German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
  • 8. Tübingen Center for Academic Drug Discovery (TüCAD2), Auf der Morgenstelle 8, 72076 Tübingen, DE, Germany.
PMID: 40404564 DOI: 10.1021/acs.jmedchem.5c00884
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 kinact/KI (JNK2) = 38,200 M-1 s-1 as well as cellular isoform selectivity and a clean kinome profile.

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