Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations.
EGFR
allosteric
combination treatment
degrader
drug-resistant mutation
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
17 08 2020
17 08 2020
Historique:
received:
07
03
2020
revised:
11
05
2020
pubmed:
9
6
2020
medline:
16
3
2021
entrez:
9
6
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32510788
doi: 10.1002/anie.202003500
pmc: PMC7686272
mid: NIHMS1623961
doi:
Substances chimiques
Protein Kinase Inhibitors
0
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
14481-14489Subventions
Organisme : NCI NIH HHS
ID : P01 CA154303
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA201049
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA221830
Pays : United States
Informations de copyright
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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