Engel, Julian, Richters, Andre, Getlik, Matthaeus, Tomassi, Stefano, Keul, Marina, Termathe, Martin ORCID: 0000-0002-5618-4633, Lategahn, Jonas ORCID: 0000-0001-5993-7082, Becker, Christian, Mayer-Wrangowski, Svenja, Gruetter, Christian, Uhlenbrock, Niklas ORCID: 0000-0002-4489-9535, Kruell, Jasmin, Schaumann, Niklas, Eppmann, Simone, Kibies, Patrick, Hoffgaard, Franziska, Heil, Jochen, Menninger, Sascha, Ortiz-Cuaran, Sandra, Heuckmann, Johannes M., Tinnefeld, Verena, Zahedi, Rene P., Sos, Martin L., Schultz-Fademrecht, Carsten, Thomas, Roman K., Kast, Stefan M. and Rauh, Daniel ORCID: 0000-0002-1970-7642 (2015). Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach. J. Med. Chem., 58 (17). S. 6844 - 6864. WASHINGTON: AMER CHEMICAL SOC. ISSN 1520-4804

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Abstract

Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds. Using protein X-ray crystallography, we deciphered the binding mode in engineered cSrc (T338M/S345C), a validated model system for EGFR-T790M, which constituted the basis for further rational design approaches. Chemical synthesis led to further compound collections that revealed increased biochemical potency and, in part, selectivity toward mutated (L858R and L858R/T790M) vs nonmutated EGFR. Further cell-based and kinetic studies were performed to substantiate our initial findings. Utilizing proteolytic digestion and nano-LC-MS/MS analysis, we confirmed the alkylation of Cys797.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Engel, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richters, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Getlik, MatthaeusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tomassi, StefanoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keul, MarinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Termathe, MartinUNSPECIFIEDorcid.org/0000-0002-5618-4633UNSPECIFIED
Lategahn, JonasUNSPECIFIEDorcid.org/0000-0001-5993-7082UNSPECIFIED
Becker, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayer-Wrangowski, SvenjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gruetter, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uhlenbrock, NiklasUNSPECIFIEDorcid.org/0000-0002-4489-9535UNSPECIFIED
Kruell, JasminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaumann, NiklasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eppmann, SimoneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kibies, PatrickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffgaard, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heil, JochenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menninger, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortiz-Cuaran, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heuckmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tinnefeld, VerenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zahedi, Rene P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schultz-Fademrecht, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kast, Stefan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDorcid.org/0000-0002-1970-7642UNSPECIFIED
URN: urn:nbn:de:hbz:38-393084
DOI: 10.1021/acs.jmedchem.5b01082
Journal or Publication Title: J. Med. Chem.
Volume: 58
Number: 17
Page Range: S. 6844 - 6864
Date: 2015
Publisher: AMER CHEMICAL SOC
Place of Publication: WASHINGTON
ISSN: 1520-4804
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; INTEGRAL-EQUATION THEORY; PHASE-II TRIAL; KINASE INHIBITORS; TYROSINE KINASE; IRREVERSIBLE INHIBITORS; MAXIMUM-LIKELIHOOD; MOLECULAR-DYNAMICS; RESIDENCE TIMEMultiple languages
Chemistry, MedicinalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/39308

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