Journal Article

DKFZ-2024-02714

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Design, Synthesis, and Biochemical Evaluation of Novel MLK3 Inhibitors: A Target Hopping Example.

Sander, P. ; Schwalm, M. P.DKFZ* ; Krämer, A. ; Elson, L. ; Rasch, A. ; Masberg, B. ; Selig, R. ; Sievers-Engler, A. ; Lämmerhofer, M. ; Müller, S. ; Knapp, S.DKFZ* ; Albrecht, W. ; Laufer, S. A.DKFZ*

2025
ACS Washington, DC

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Please use a persistent id in citations: 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.

Note: 2025, 68, 1, 674–694

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Frankfurt (FM01)
2. DKTK Koordinierungsstelle Tübingen (TU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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