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

Autor:	Sander P; Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, Tuebingen 72076, Germany., Schwalm MP; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DTKT Site Frankfurt-Mainz, Heidelberg 69120, Germany., Krämer A; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany., Elson L; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany., Rasch A; Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, Tuebingen 72076, Germany., Masberg B; Pharmaceutical (Bio-)Analysis, Institute of Pharmaceutical Sciences, Eberhard-Karls University of Tuebingen, Auf der Morgenstelle 8, Tuebingen 72076, Germany., Selig R; Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, Tuebingen 72076, Germany.; HepaRegeniX GmbH, Eisenbahnstraße 63, Tuebingen 72072, Germany., Sievers-Engler A; Pharmaceutical (Bio-)Analysis, Institute of Pharmaceutical Sciences, Eberhard-Karls University of Tuebingen, Auf der Morgenstelle 8, Tuebingen 72076, Germany., Lämmerhofer M; Pharmaceutical (Bio-)Analysis, Institute of Pharmaceutical Sciences, Eberhard-Karls University of Tuebingen, Auf der Morgenstelle 8, Tuebingen 72076, Germany., Müller S; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany., Knapp S; Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, Frankfurt am Main 60438, Germany.; Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, Frankfurt am Main 60438, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DTKT Site Frankfurt-Mainz, Heidelberg 69120, Germany., Albrecht W; HepaRegeniX GmbH, Eisenbahnstraße 63, Tuebingen 72072, Germany., Laufer SA; Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tuebingen, Auf der Morgenstelle 8, Tuebingen 72076, Germany.; Cluster of Excellence 'Image Guided and Functionally Instructed Tumor Therapies' (iFIT), Eberhard Karls University of Tuebingen, Tuebingen 72076, Germany.; German Consortium for Translational Cancer Research (DKTK), Partner Site Tuebingen, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.; Tuebingen Center for Academic Drug Discovery, Auf der Morgenstelle 8, Tuebingen 72076, Germany.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Dec 16. Date of Electronic Publication: 2024 Dec 16.
DOI:	10.1021/acs.jmedchem.4c02552
Abstrakt:	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 IC 50 value of <1 nM in a biochemical MLK3 assay while simultaneously exhibiting kinome-wide selectivity.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu