TY  - JOUR
AU  - Dimitrov, Teodor
AU  - Moschopoulou, Athina Anastasia
AU  - Seidel, Lennart
AU  - Kronenberger, Thales
AU  - Kudolo, Mark
AU  - Poso, Antti
AU  - Geibel, Christian
AU  - Wölffing, Pascal
AU  - Dauch, Daniel
AU  - Zender, Lars
AU  - Schollmeyer, Dieter
AU  - Bajorath, Jürgen
AU  - Forster, Michael
AU  - Laufer, Stefan
TI  - Design and Optimization of Novel Benzimidazole- and Imidazo[4,5-b]pyridine-Based ATM Kinase Inhibitors with Subnanomolar Activities.
JO  - Journal of medicinal chemistry
VL  - 66
IS  - 11
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - DKFZ-2023-01036
SP  - 7304-7330
PY  - 2023
N1  - 2023 Jun 8;66(11):7304-7330
AB  - The ATM kinase is a promising target in cancer treatment as an important regulator of the cellular response to DNA double-strand breaks. In this work, we present a new class of specific benzimidazole-based ATM inhibitors with picomolar potency against the isolated enzyme and favorable selectivity within relative PIKK and PI3K kinases. We could identify two promising inhibitor subgroups with significantly different physicochemical properties, which we developed simultaneously. These efforts lead to numerous highly active inhibitors with picomolar enzymatic activities. Furthermore, initial low cellular activities on A549 cells could be increased significantly in numerous examples resulting in cellular IC50 values in the subnanomolar range. Further characterization of the highly potent inhibitors 90 und 93 revealed promising pharmacokinetic properties and strong activities in organoids in combination with etoposide. Additionally, 93 showed no off-target activities within a kinome-representative mini kinase panel, with favorable selectivities within the PIKK- and PI3K-families.
LB  - PUB:(DE-HGF)16
C6  - pmid:37226670
DO  - DOI:10.1021/acs.jmedchem.2c02104
UR  - https://inrepo02.dkfz.de/record/276227
ER  -