Engel, Julian, Smith, Steven, Lategahn, Jonas ORCID: 0000-0001-5993-7082, Turnbrink, Hannah L., Goebel, Lisa, Becker, Christian, Hennes, Elisabeth, Keul, Marina, Unger, Anke, Mueller, Heiko, Baumann, Matthias, Schultz-Fademrecht, Carsten, Guenther, Georgia, Hengstler, Jan G. and Rauh, Daniel (2017). Structure-Guided Development of Covalent and Mutant-Selective Pyrazolopyrimidines to Target T790M Drug Resistance in Epidermal Growth Factor Receptor. J. Med. Chem., 60 (18). S. 7725 - 7745. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-4804

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Abstract

Reversible epidermal growth factor receptor (BUR) inhibitors prompt a beneficial clinical response in non-small cell lung cancer patients-who harbor activating mutations in EGFR. However, resistance mutations, particularly the gatekeeper mutation T790M, limit this efficacy. Here, we describe a structure-guided development of a series of covalent and mutant-selective EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based core differs structurally from that of aminopyrimidine-based third-generation EGFR inhibitors and therefore constitutes a new set of inhibitors that target this mechanism of drug resistance. These inhibitors exhibited strong inhibitory effects toward EGFR kinase activity and excellent inhibition of cell growth in the drug resistant cell line H1975, without significantly affecting EGFR wild-type cell lines. Additionally, we present the in vitro ADME/DMPR parameters for a subset of the inhibitors as well as in vivo pharmacokinetics in mice for a candidate with promising activity profile.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Engel, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, StevenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lategahn, JonasUNSPECIFIEDorcid.org/0000-0001-5993-7082UNSPECIFIED
Turnbrink, Hannah L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goebel, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hennes, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keul, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Unger, AnkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schultz-Fademrecht, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenther, GeorgiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hengstler, Jan G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-217378
DOI: 10.1021/acs.jmedchem.7b00515
Journal or Publication Title: J. Med. Chem.
Volume: 60
Number: 18
Page Range: S. 7725 - 7745
Date: 2017
Publisher: AMER CHEMICAL SOC
Place of Publication: WASHINGTON
ISSN: 1520-4804
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL LUNG-CANCER; TYROSINE KINASE INHIBITOR; PHASE-II TRIAL; EGFR MUTATIONS; IRREVERSIBLE INHIBITORS; INCREASED SENSITIVITY; GEFITINIB; ROCILETINIB; DISCOVERY; CHEMOTHERAPYMultiple languages
Chemistry, MedicinalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21737

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