TY  - JOUR
AU  - Katzengruber, Leon
AU  - Sander, Pascal
AU  - Zwirner, Stefan
AU  - Rasch, Alexander
AU  - Eberlein, Eric
AU  - Selig, Roland
AU  - Albrecht, Wolfgang
AU  - Zender, Lars
AU  - Laufer, Stefan A
TI  - Discovery of the First Highly Selective 1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one MKK4 Inhibitor.
JO  - Journal of medicinal chemistry
VL  - 68
IS  - 14
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - DKFZ-2025-01378
SP  - 14782-14805
PY  - 2025
N1  - 2025 Jul 24;68(14):14782-14805
AB  - Due to limited treatment options, liver failure remains a major challenge in modern medicine. With the validation of mitogen-activated protein kinase kinase 4 (MKK4, also known as MEK4 or MAP2K4) as a regulator of hepatocyte regeneration, a promising target for curative treatment of degenerative liver diseases was recently identified via in vivo RNAi experiments. The field of small molecules targeting MKK4 is of growing interest. Several MKK4 inhibitors with differing scaffolds are known, but few have reasonable selectivity profiles and drug-like properties. To further explore the space of drug-like MKK4 scaffolds, we performed a broad screening campaign and identified BI-D1870 as a promising candidate. The dihydropteridinone BI-D1870 is an unselective ribosomal S6 kinase inhibitor with broad off-target activity. In the study presented herein, we report a successful off-to-on target strategy that led to the development of highly selective 1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one inhibitors of MKK4.
LB  - PUB:(DE-HGF)16
C6  - pmid:40643363
DO  - DOI:10.1021/acs.jmedchem.5c00919
UR  - https://inrepo02.dkfz.de/record/302838
ER  -