Lategahn, Jonas ORCID: 0000-0001-5993-7082, Keul, Marina, Kloevekorn, Philip, Tumbrink, Hannah L., Niggenaber, Janina ORCID: 0000-0003-2942-263X, Mueller, Matthias P., Hodson, Luke, Flasshoff, Maren, Hardick, Julia, Grabe, Tobias, Engel, Julian, Schultz-Fademrecht, Carsten, Baumann, Matthias, Ketzer, Julia, Muehlenberg, Thomas, Hiller, Wolf, Guenther, Georgia, Unger, Anke, Mueller, Heiko, Heimsoeth, Alena, Golz, Christopher, Blank-Landeshammer, Bernhard, Kollipara, Laxmikanth, Zahedi, Rene P., Strohmann, Carsten ORCID: 0000-0002-4787-2135, Hengstler, Jan G., van Otterlo, Willem A. L., Bauer, Sebastian ORCID: 0000-0001-5949-8120 and Rauh, Daniel (2019). Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S. Chem. Sci., 10 (46). S. 10789 - 10802. CAMBRIDGE: ROYAL SOC CHEMISTRY. ISSN 2041-6539

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Abstract

Precision medicine has revolutionized the treatment of patients in EGFR driven non-small cell lung cancer (NSCLC). Targeted drugs show high response rates in genetically defined subsets of cancer patients and markedly increase their progression-free survival as compared to conventional chemotherapy. However, recurrent acquired drug resistance limits the success of targeted drugs in long-term treatment and requires the constant development of novel efficient inhibitors of drug resistant cancer subtypes. Herein, we present covalent inhibitors of the drug resistant gatekeeper mutant EGFR-L858R/T790M based on the pyrrolopyrimidine scaffold. Biochemical and cellular characterization, as well as kinase selectivity profiling and western blot analysis, substantiate our approach. Moreover, the developed compounds possess high activity against multi drug resistant EGFR-L858R/T790M/C797S in biochemical assays due to their highly reversible binding character, that was revealed by characterization of the binding kinetics. In addition, we present the first X-ray crystal structures of covalent inhibitors in complex with C797S-mutated EGFR which provide detailed insight into their binding mode.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lategahn, JonasUNSPECIFIEDorcid.org/0000-0001-5993-7082UNSPECIFIED
Keul, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloevekorn, PhilipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tumbrink, Hannah L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niggenaber, JaninaUNSPECIFIEDorcid.org/0000-0003-2942-263XUNSPECIFIED
Mueller, Matthias P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hodson, LukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Flasshoff, MarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hardick, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grabe, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schultz-Fademrecht, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ketzer, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muehlenberg, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hiller, WolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenther, GeorgiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Unger, AnkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heimsoeth, AlenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Golz, ChristopherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blank-Landeshammer, BernhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kollipara, LaxmikanthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zahedi, Rene P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strohmann, CarstenUNSPECIFIEDorcid.org/0000-0002-4787-2135UNSPECIFIED
Hengstler, Jan G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Otterlo, Willem A. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bauer, SebastianUNSPECIFIEDorcid.org/0000-0001-5949-8120UNSPECIFIED
Rauh, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-124410
DOI: 10.1039/c9sc03445e
Journal or Publication Title: Chem. Sci.
Volume: 10
Number: 46
Page Range: S. 10789 - 10802
Date: 2019
Publisher: ROYAL SOC CHEMISTRY
Place of Publication: CAMBRIDGE
ISSN: 2041-6539
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL LUNG-CANCER; OVERCOME DRUG-RESISTANCE; EGFR INHIBITORS; C797S MUTATION; OPEN-LABEL; COVALENT INHIBITORS; 1ST-LINE TREATMENT; GEFITINIB; MUTANT; CHEMOTHERAPYMultiple languages
Chemistry, MultidisciplinaryMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/12441

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