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Molecular Design of a “Two-in-One” Orthosteric-Allosteric Chimeric Mutant Selective EGFR Inhibitor

submitted on 18.12.2020, 15:14 and posted on 21.12.2020, 12:56 by Florian Wittlinger, david heppner, Ciric To, Marcel Guenther, Bo Hee Shin, Jaimin K. Rana, Anna M. Schmoker, Tyler S. Beyett, Pasi A. Jänne, Michael J. Eck, Stefan Laufer
Inhibitors developed to target the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harbouring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations within the receptor itself has motivated development of successive generations of inhibitors that bind in the ATP-site, and third-generation agent osimertinib is now a first-line treatment for this disease. More recently, allosteric inhibitors have been developed to overcome the C797S mutation that confers resistance to osimertinib. In this study, we present the rational structure-guided design and synthesis of a mutant-selective EGFR inhibitor that spans the ATPand allosteric sites. The lead compound consists of a pyridinyl imidazole scaffold that binds irreversibly in the orthosteric site fused with a benzylisoindolinedione occupying the allosteric site. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with relative sparing of wild-type EGFR (47 nM). Additionally, this compound achieves cetuximab-independent, mutant-selective cellular efficacy on the L858R and L858R/T790M variants


Email Address of Submitting Author


Eberhard-Karls-University Tuebingen



ORCID For Submitting Author


Declaration of Conflict of Interest



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