2. Academic Validation
  3. Design, Synthesis, and Biochemical Evaluation of Novel MLK3 Inhibitors: A Target Hopping Example

Design, Synthesis, and Biochemical Evaluation of Novel MLK3 Inhibitors: A Target Hopping Example

  • J Med Chem. 2025 Jan 9;68(1):674-694. doi: 10.1021/acs.jmedchem.4c02552.
Pascal Sander 1,  Martin P Schwalm 2 3 4,  Andreas Krämer 2 3,  Lewis Elson 2 3,  Alexander Rasch 1,  Benedikt Masberg 5,  Roland Selig 1 6,  Adrian Sievers-Engler 5,  Michael Lämmerhofer 5,  Susanne Müller 2 3,  Stefan Knapp 2 3 4,  Wolfgang Albrecht 6,  Stefan A Laufer 1 7 8 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, Tuebingen 72076, Germany.
  • 2 Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.
  • 3 Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany.
  • 4 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DTKT Site Frankfurt-Mainz, Heidelberg 69120, Germany.
  • 5 Pharmaceutical (Bio-)Analysis, Institute of Pharmaceutical Sciences, Eberhard-Karls University of Tuebingen, Auf der Morgenstelle 8, Tuebingen 72076, Germany.
  • 6 HepaRegeniX GmbH, Eisenbahnstraße 63, Tuebingen 72072, Germany.
  • 7 Cluster of Excellence "Image Guided and Functionally Instructed Tumor Therapies" (iFIT), Eberhard Karls University of Tuebingen, Tuebingen 72076, Germany.
  • 8 German Consortium for Translational Cancer Research (DKTK), Partner Site Tuebingen, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • 9 Tuebingen Center for Academic Drug Discovery, Auf der Morgenstelle 8, Tuebingen 72076, Germany.
PMID: 39681301 DOI: 10.1021/acs.jmedchem.4c02552
Abstract

The human kinome has tremendous medical potential. In the past decade, mixed-lineage protein kinase 3 (MLK3) has emerged as an interesting and druggable target in oncogenic signaling. The important role of MLK3 has been demonstrated in several types of Cancer. In a target hopping example we started with the focal adhesion kinase (FAK) inhibitor PF-431396 (10), which shows off-target activity toward MLK3. We were able to develop highly active compounds in the single digit nanomolar range for MLK3. Furthermore, we achieved a dramatic shift in selectivity from FAK to MLK3. Here we present a new chemical class of MLK3 inhibitors, including our lead compound 37 with an outstanding IC50 value of <1 nM in a biochemical MLK3 assay while simultaneously exhibiting kinome-wide selectivity.

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