2. Academic Validation
  3. Discovery of the First Highly Selective 1,4-dihydropyrido[3,4- b]pyrazin-3(2H)-one MKK4 Inhibitor

Discovery of the First Highly Selective 1,4-dihydropyrido[3,4- b]pyrazin-3(2H)-one MKK4 Inhibitor

  • J Med Chem. 2025 Jul 24;68(14):14782-14805. doi: 10.1021/acs.jmedchem.5c00919.
Leon Katzengruber 1 2,  Pascal Sander 1,  Stefan Zwirner 3 4,  Alexander Rasch 1,  Eric Eberlein 1,  Roland Selig 1 4,  Wolfgang Albrecht 4,  Lars Zender 3 5 6 7,  Stefan A Laufer 1 5 6 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, Tübingen 72076, Germany.
  • 2 Department of Chemical and Systems Biology, Stanford University, 290 Jane Stanford Way, Stanford, California 94305, United States.
  • 3 Department of Medical Oncology and Pneumology (Internal Medicine VIII), University Hospital Tübingen,, Tübingen 72076, Germany.
  • 4 HepaRegenix GmbH, Eisenbahnstraße 63, Tübingen 72072, Germany.
  • 5 IFIT Cluster of Excellence (EXC2180) "Image Guided and Functionally Instructed Tumor Therapies", Eberhard Karls University of Tübingen, Tübingen 72076, Germany.
  • 6 German Cancer Research Center (DKFZ), German Consortium for Translational Cancer Research (DKTK), Partner Site Tübingen, Heidelberg 69120, Germany.
  • 7 Tübingen Center for Academic Drug Discovery & Development (TüCAD2), Auf der Morgenstelle 8, Tübingen 72076, Germany.
PMID: 40643363 DOI: 10.1021/acs.jmedchem.5c00919
Abstract

Due to limited treatment options, liver failure remains a major challenge in modern medicine. With the validation of mitogen-activated protein kinase kinase 4 (MKK4, also known as MEK4 or MAP2K4) as a regulator of hepatocyte regeneration, a promising target for curative treatment of degenerative liver diseases was recently identified via in vivo RNAi experiments. The field of small molecules targeting MKK4 is of growing interest. Several MKK4 inhibitors with differing scaffolds are known, but few have reasonable selectivity profiles and drug-like properties. To further explore the space of drug-like MKK4 scaffolds, we performed a broad screening campaign and identified BI-D1870 as a promising candidate. The dihydropteridinone BI-D1870 is an unselective ribosomal S6 kinase inhibitor with broad off-target activity. In the study presented herein, we report a successful off-to-on target strategy that led to the development of highly selective 1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one inhibitors of MKK4.

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