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Mutant‐Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug‐Resistant Mutations
Author(s) -
Jang Jaebong,
To Ciric,
De Clercq Dries J. H.,
Park Eunyoung,
Ponthier Charles M.,
Shin Bo Hee,
Mushajiang Mierzhati,
Nowak Radosław P.,
Fischer Eric S.,
Eck Michael J.,
Jänne Pasi A.,
Gray Nathanael S.
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202003500
Subject(s) - allosteric regulation , t790m , osimertinib , epidermal growth factor receptor , mutant , chemistry , egfr inhibitors , drug , cancer research , biology , pharmacology , receptor , biochemistry , erlotinib , gefitinib , gene
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.