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Download fileIndazole-Based Covalent Inhibitors To Target Drug-Resistant Epidermal Growth Factor Receptor
journal contribution
posted on 2017-02-22, 00:00 authored by Stefano Tomassi, Jonas Lategahn, Julian Engel, Marina Keul, Hannah L. Tumbrink, Julia Ketzer, Thomas Mühlenberg, Matthias Baumann, Carsten Schultz-Fademrecht, Sebastian Bauer, Daniel RauhThe specific targeting of oncogenic
mutant epidermal growth factor
receptor (EGFR) is a breakthrough in targeted cancer therapy and marks
a drastic change in the treatment of non-small cell lung cancer (NSCLC).
The recurrent emergence of resistance to these targeted drugs requires
the development of novel chemical entities that efficiently inhibit
drug-resistant EGFR. Herein, we report the optimization process for
a hit compound that has emerged from a phenotypic screen resulting
in indazole-based compounds. These inhibitors are conformationally
less flexible, target gatekeeper mutated drug-resistant EGFR-L858R/T790M,
and covalently alkylate Cys797. Western blot analysis, as well as
characterization of the binding kinetics and kinase selectivity profiling,
substantiates our approach of targeting drug-resistant EGFR-L858R/T790M
with inhibitors incorporating the indazole as hinge binder.
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non-small cell lung cancernovel chemical entitiesbinding kineticskinase selectivitycovalently alkylate Cys 797.target gatekeeperTarget Drug-Resistant Epidermal Growth Factor Receptoroptimization processepidermal growth factor receptorinhibitorphenotypic screenNSCLCdrug-resistant EGFRblot analysisindazole-based compoundsdrug-resistant EGFR-L 858RIndazole-Based Covalent Inhibitorscancer therapy