Development of novel urea-based ATM kinase inhibitors with subnanomolar cellular potency and high kinome selectivity.

Ataxia Telangiectasia Mutated Proteins Cell Line, Tumor DNA Damage Protein Kinase Inhibitors / chemistry Proteins / metabolism Urea / pharmacology
ATM kinase ATM kinase inhibitors Cancer DDR pathway MD simulation PIKK

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
05 May 2022
Historique:
received: 23 12 2021
revised: 22 02 2022
accepted: 23 02 2022
pubmed: 25 3 2022
medline: 26 4 2022
entrez: 24 3 2022
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ejmech.2022.114234 PMID: 35325634
pubmed: 35325634
pii: S0223-5234(22)00136-2
doi: 10.1016/j.ejmech.2022.114234
pii:
doi:

Substances chimiques

Protein Kinase Inhibitors 0
Proteins 0
Urea 8W8T17847W
Ataxia Telangiectasia Mutated Proteins EC 2.7.11.1

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

114234

Informations de copyright

Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Stefan Laufer has patent pending to DKFZ, German Cancer Research Center. Michael Forster has patent pending to DKFZ, German Cancer Research Center. Teodor Dimitrov has patent pending to DKFZ, German Cancer Research Center. Athina Anastasia Moschopoulou has patent pending to DKFZ, German Cancer Research Center. Lars Zender has patent pending to DKFZ, German Cancer Research Center.

Auteurs

Teodor Dimitrov (T)

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 (C)

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, 72076, Tübingen, Germany.

Athina Anastasia Moschopoulou (AA)

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 (T)

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 (M)

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, 72076, Tübingen, Germany.

Christian Geibel (C)

Department of Pharmaceutical (Bio-)Analysis, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, 72076, Tübingen, Germany.

Martin Peter Schwalm (MP)

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 (S)

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 (L)

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 (M)

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 (S)

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.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Protéines liant le poly-adp-ribose › Protéines mutées dans l'ataxie-télangiectasie › Development of novel urea-based ATM kinase...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Development of novel urea-based ATM kinase...
questionsmedicales.fr › Phénomènes génétiques › Altération de l'ADN › Development of novel urea-based ATM kinase...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Development of novel urea-based ATM kinase...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Development of novel urea-based ATM kinase...
questionsmedicales.fr › Composés chimiques organiques › Amides › Urée › Development of novel urea-based ATM kinase...