%0 Journal Article
%A Sander, Pascal
%A Schwalm, Martin P
%A Krämer, Andreas
%A Elson, Lewis
%A Rasch, Alexander
%A Masberg, Benedikt
%A Selig, Roland
%A Sievers-Engler, Adrian
%A Lämmerhofer, Michael
%A Müller, Susanne
%A Knapp, Stefan
%A Albrecht, Wolfgang
%A Laufer, Stefan A
%T Design, Synthesis, and Biochemical Evaluation of Novel MLK3 Inhibitors: A Target Hopping Example.
%J Journal of medicinal chemistry
%V 68
%N 1
%@ 0095-9065
%C Washington, DC
%I ACS
%M DKFZ-2024-02714
%P 674–694
%D 2025
%Z  2025, 68, 1, 674–694
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:39681301
%R 10.1021/acs.jmedchem.4c02552
%U https://inrepo02.dkfz.de/record/295900