Journal Article

DKFZ-2023-01036

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Design and Optimization of Novel Benzimidazole- and Imidazo[4,5-b]pyridine-Based ATM Kinase Inhibitors with Subnanomolar Activities.

Dimitrov, T. ; Moschopoulou, A. A.DKFZ* ; Seidel, L. ; Kronenberger, T. ; Kudolo, M. ; Poso, A. ; Geibel, C. ; Wölffing, P. ; Dauch, D. ; Zender, L.DKFZ* ; Schollmeyer, D. ; Bajorath, J. ; Forster, M. ; Laufer, S.DKFZ*

2023
ACS Washington, DC

Abstract: 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.

Note: 2023 Jun 8;66(11):7304-7330

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Tübingen (TU01)

Research Program(s):

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

Appears in the scientific report 2023

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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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