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

Authors
Jang, JaebongTo, CiricDe Clercq, Dries J. H.Park, EunyoungPonthier, Charles M.Shin, Bo HeeMushajiang, MierzhatiNowak, Radoslaw P.Fischer, Eric S.Eck, Michael J.Janne, Pasi A.Gray, Nathanael S.
Issue Date
17-8월-2020
Publisher
WILEY-V C H VERLAG GMBH
Keywords
allosteric; combination treatment; degrader; drug-resistant mutation; EGFR
Citation
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, v.59, no.34, pp.14481 - 14489
Indexed
SCIE
SCOPUS
Journal Title
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume
59
Number
34
Start Page
14481
End Page
14489
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/53755
DOI
10.1002/anie.202003500
ISSN
1433-7851
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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