Design and Optimization of Novel Benzimidazole- and Imidazo[4,5-]pyridine-Based ATM Kinase Inhibitors with Subnanomolar Activities.
Teodor Dimitrov, Athina Anastasia Moschopoulou, Lennart Seidel, Thales Kronenberger, Mark Kudolo, Antti Poso, Christian Geibel, Pascal Wölffing, Daniel Dauch, Lars Zender, Dieter Schollmeyer, Jürgen Bajorath, Michael Forster, Stefan Laufer
Author Information
Teodor Dimitrov: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, Tübingen 72076, Germany.
Athina Anastasia Moschopoulou: Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen 72076, Germany.
Lennart Seidel: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, Tübingen 72076, Germany.
Thales Kronenberger: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, Tübingen 72076, Germany.
Mark Kudolo: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, Tübingen 72076, Germany.
Antti Poso: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, Tübingen 72076, Germany. ORCID
Christian Geibel: Department of Pharmaceutical (Bio-)Analysis, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, Tübingen 72076, Germany. ORCID
Pascal Wölffing: Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen 72076, Germany.
Daniel Dauch: Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen 72076, Germany. ORCID
Lars Zender: Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen 72076, Germany.
Dieter Schollmeyer: Department Chemie, Johannes Gutenberg-Universitaet Mainz, Zentrale Analytik, Duesbergweg 10-14, Mainz 55099, Germany.
Jürgen Bajorath: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität Bonn, Friedrich-Hirzebruch-Allee 5/6, Bonn D-53115, Germany. ORCID
Michael Forster: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, Tübingen 72076, Germany.
Stefan Laufer: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, Tübingen 72076, Germany. ORCID
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 IC values in the subnanomolar range. Further characterization of the highly potent inhibitors und revealed promising pharmacokinetic properties and strong activities in organoids in combination with etoposide. Additionally, showed no off-target activities within a kinome-representative mini kinase panel, with favorable selectivities within the PIKK- and PI3K-families.
