Issue 46, 2019

Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S


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.

Graphical abstract: Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S

Supplementary files

Article information

Article type
Edge Article
12 Jul 2019
03 Oct 2019
First published
04 Oct 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2019,10, 10789-10801

Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S

J. Lategahn, M. Keul, P. Klövekorn, H. L. Tumbrink, J. Niggenaber, M. P. Müller, L. Hodson, M. Flaßhoff, J. Hardick, T. Grabe, J. Engel, C. Schultz-Fademrecht, M. Baumann, J. Ketzer, T. Mühlenberg, W. Hiller, G. Günther, A. Unger, H. Müller, A. Heimsoeth, C. Golz, B. Blank-Landeshammer, L. Kollipara, R. P. Zahedi, C. Strohmann, J. G. Hengstler, W. A. L. van Otterlo, S. Bauer and D. Rauh, Chem. Sci., 2019, 10, 10789 DOI: 10.1039/C9SC03445E

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