Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations.

Angewandte Chemie
Jaebong JangNathanael S Gray

Abstract

Targeting epidermal growth factor receptor (EGFR) through an allosteric mechanism provides a potential therapeutic strategy to overcome drug-resistant EGFR mutations that emerge within the ATP binding site. Here, we develop an allosteric EGFR degrader, DDC-01-163, which can selectively inhibit the proliferation of L858R/T790M (L/T) mutant Ba/F3 cells while leaving wildtype EGFR Ba/F3 cells unaffected. DDC-01-163 is also effective against osimertinib-resistant cells with L/T/C797S and L/T/L718Q EGFR mutations. When combined with an ATP-site EGFR inhibitor, osimertinib, the anti-proliferative activity of DDC-01-163 against L858R/T790M EGFR-Ba/F3 cells is enhanced. Collectively, DDC-01-163 is a promising allosteric EGFR degrader with selective activity against various clinically relevant EGFR mutants as a single agent and when combined with an ATP-site inhibitor. Our data suggests that targeted protein degradation is a promising drug development approach for mutant EGFR.

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Citations

Jun 1, 2021·Expert Opinion on Drug Discovery·Florian Wittlinger, Stefan A Laufer
Aug 6, 2021·Frontiers in Cell and Developmental Biology·Jing LiuWenyi Wei
Sep 8, 2021·Journal of Medicinal Chemistry·M Raymond V FinlayXiliang Zhao
Oct 28, 2021·Expert Opinion on Therapeutic Patents·Alexander Kazantsev, Mikhail Krasavin
Dec 25, 2021·Future Medicinal Chemistry·Fabian FischerThomas Kurz
Jun 3, 2021·Biomolecules & Therapeutics·Krishna Babu DuggiralaKwangho Lee

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