Targeting Drug Resistance in EGFR with Covalent Inhibitors: A Structure-Based Design Approach

J Med Chem. 2015 Sep 10;58(17):6844-63. doi: 10.1021/acs.jmedchem.5b01082.

Julian Engel ¹, André Richters ¹, Matthäus Getlik ², Stefano Tomassi ¹, Marina Keul ¹, Martin Termathe ², Jonas Lategahn ¹, Christian Becker ¹, Svenja Mayer-Wrangowski ¹, Christian Grütter ¹, Niklas Uhlenbrock ¹, Jasmin Krüll ¹, Niklas Schaumann ¹, Simone Eppmann ¹, Patrick Kibies ¹, Franziska Hoffgaard ¹, Jochen Heil ¹, Sascha Menninger ³, Sandra Ortiz-Cuaran ⁴, Johannes M Heuckmann ⁴, Verena Tinnefeld ⁵, René P Zahedi ⁵, Martin L Sos ⁴ ⁶, Carsten Schultz-Fademrecht ³, Roman K Thomas ⁴ ⁷, Stefan M Kast ¹, Daniel Rauh ¹ ²

Affiliations

1 Department of Chemistry and Chemical Biology, TU Dortmund University , Otto-Hahn-Straße 6, D-44227 Dortmund, Germany.
2 Chemical Genomics Centre of the Max-Planck Society , Otto-Hahn-Straße 15, D-44227 Dortmund, Germany.
3 Lead Discovery Center GmbH , Otto-Hahn-Straße 15, D-44227 Dortmund, Germany.
4 Department of Translational Genomics, Medical Faculty, University of Cologne , Weyertal 115b, D-50931 Cologne, Germany.
5 Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V. , D-44139 Dortmund, Germany.
6 Molecular Pathology, University Hospital of Cologne , Kerpenerstraße 62, D-50937 Cologne, Germany.
7 Department of Pathology, University of Cologne , Joseph-Stelzmann Straße 9, D-50931 Cologne, Germany.

PMID: 26275028 DOI: 10.1021/acs.jmedchem.5b01082

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.

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