TY  - JOUR
AU  - Sander, Pascal
AU  - Schwalm, Martin P
AU  - Krämer, Andreas
AU  - Elson, Lewis
AU  - Rasch, Alexander
AU  - Masberg, Benedikt
AU  - Selig, Roland
AU  - Sievers-Engler, Adrian
AU  - Lämmerhofer, Michael
AU  - Müller, Susanne
AU  - Knapp, Stefan
AU  - Albrecht, Wolfgang
AU  - Laufer, Stefan A
TI  - Design, Synthesis, and Biochemical Evaluation of Novel MLK3 Inhibitors: A Target Hopping Example.
JO  - Journal of medicinal chemistry
VL  - 68
IS  - 1
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - DKFZ-2024-02714
SP  - 674–694
PY  - 2025
N1  -  2025, 68, 1, 674–694
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:39681301
DO  - DOI:10.1021/acs.jmedchem.4c02552
UR  - https://inrepo02.dkfz.de/record/295900
ER  -