Sulfoximines as ATR inhibitors: Analogs of VE-821

Christine M M Hendriks; Jörg Hartkamp; Stefan Wiezorek; Anne-Dorothee Steinkamp; Giulia Rossetti; Bernhard Lüscher; Carsten Bolm

doi:10.1016/j.bmcl.2017.04.026

Sulfoximines as ATR inhibitors: Analogs of VE-821

Bioorg Med Chem Lett. 2017 Jun 15;27(12):2659-2662. doi: 10.1016/j.bmcl.2017.04.026. Epub 2017 Apr 8.

Authors

Christine M M Hendriks¹, Jörg Hartkamp², Stefan Wiezorek¹, Anne-Dorothee Steinkamp¹, Giulia Rossetti³, Bernhard Lüscher², Carsten Bolm⁴

Affiliations

¹ Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056 Aachen, Germany.
² Institute of Biochemistry and Molecular Biology, Medical School, RWTH Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germany.
³ Department of Oncology, Hematology and Stem Cell Transplantation, Medical School, RWTH Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germany; IAS-5/INM-9: Computational Biomedicine - Institute for Advanced Simulation (IAS)/Institute of Neuroscience and Medicine (INM) and Jülich Supercomputing Centre (JSC), Forschungszentrum Jülich, D-52425 Jülich, Germany.
⁴ Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056 Aachen, Germany. Electronic address: Carsten.Bolm@oc.rwth-aachen.de.

PMID: 28479198
DOI: 10.1016/j.bmcl.2017.04.026

Abstract

The ATM- and Rad3-related (ATR) kinases play a key role in DNA repair processes and thus ATR is an attractive target for cancer therapy. Here we designed and synthesized sulfilimidoyl- and sulfoximidoyl-substituted analogs of the sulfone VE-821, a reported ATR inhibitor. The properties of these analogs have been investigated by calculating physicochemical parameters and studying their potential to specifically inhibit ATR in cells. Prolonged inhibition of ATR by the analogs in a Burkitt lymphoma cell line resulted in enhanced DNA damage and a substantial amount of apoptosis. Together our findings suggest that the sulfilimidoyl- and sulfoximidoyl-substituted analogs are efficient ATR inhibitors.

Keywords: ATR inhibition; DNA repair; MYC; Oncogene; Replication; Stress; Sulfoximine; VE-821.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects
Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
Ataxia Telangiectasia Mutated Proteins / metabolism
Cell Line, Tumor
DNA Damage
Dose-Response Relationship, Drug
Humans
Imines / chemical synthesis
Imines / chemistry
Imines / pharmacology*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrazines / chemical synthesis
Pyrazines / chemistry
Pyrazines / pharmacology*
Structure-Activity Relationship
Sulfones / chemical synthesis
Sulfones / chemistry
Sulfones / pharmacology*

Substances

3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide
Imines
Protein Kinase Inhibitors
Pyrazines
Sulfones
ATR protein, human
Ataxia Telangiectasia Mutated Proteins