Development of novel urea-based ATM kinase inhibitors with subnanomolar cellular potency and high kinome selectivity.
Teodor Dimitrov, Cetin Anli, Athina Anastasia Moschopoulou, Thales Kronenberger, Mark Kudolo, Christian Geibel, Martin Peter Schwalm, Stefan Knapp, Lars Zender, Michael Forster, Stefan Laufer
Author Information
Teodor Dimitrov: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, 72076, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076, Tübingen, Germany.
Cetin Anli: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, 72076, Tübingen, Germany.
Athina Anastasia Moschopoulou: Department of Internal Medicine VIII, University Hospital of Tübingen, 72076, Tübingen, Germany; German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Thales Kronenberger: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, 72076, Tübingen, Germany; Department of Internal Medicine VIII, University Hospital of Tübingen, 72076, Tübingen, Germany; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211, Kuopio, Finland.
Mark Kudolo: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, 72076, Tübingen, Germany.
Christian Geibel: Department of Pharmaceutical (Bio-)Analysis, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, 72076, Tübingen, Germany.
Martin Peter Schwalm: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438, Frankfurt, Germany; Structure Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Goethe University Frankfurt, 60438, Frankfurt, Germany.
Stefan Knapp: Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 60438, Frankfurt, Germany; Structure Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Goethe University Frankfurt, 60438, Frankfurt, Germany.
Lars Zender: Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076, Tübingen, Germany; Department of Internal Medicine VIII, University Hospital of Tübingen, 72076, Tübingen, Germany; German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Michael Forster: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, 72076, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076, Tübingen, Germany; German Cancer Research Consortium (DKTK), Partner Site Tübingen, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. Electronic address: michael.forster@uni-tuebingen.de.
Stefan Laufer: Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, 72076, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076, Tübingen, Germany; Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076, Tübingen, Germany. Electronic address: stefan.laufer@uni-tuebingen.de.
The ATM kinase is a key molecule regulating DNA damage response and can be targeted resulting in efficient radio- or chemosensitization. Due to the enormous size of this protein and the associated difficulties in obtaining high-quality crystal structures, we sought to develop an accurate in silico model to identify new targeting possibilities. We identified a urea group as the most beneficial chemical anchor point, which could undergo multiple interactions in the aspartate-rich hydrophobic region I of the atypical ATM kinase domain. Based on in silico data, we designed and synthesized a comprehensive set of novel urea-based inhibitors and characterized them in diverse biochemical assays. Using this strategy, we identified inhibitors with subnanomolar potency, which were further evaluated in cellular models, selectivity and early DMPK properties. Finally, the two lead compounds 34 and 39 exhibited subnanomolar cellular activity along with an excellent selectivity profile and favorable metabolic stability.
