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
  • 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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