Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC.
Allosteric inhibitor
EGFR
Kinase inhibitor
Non-small cell lung cancer
Quinazolinone
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
15 07 2022
15 07 2022
Historique:
received:
17
12
2021
revised:
28
03
2022
accepted:
30
03
2022
pubmed:
5
4
2022
medline:
25
5
2022
entrez:
4
4
2022
Statut:
ppublish
Résumé
The C797S mutation confers resistance to covalent EGFR inhibitors used in the treatment of lung tumors with the activating L858R mutation. Isoindolinones such as JBJ-4-125-02 bind in an allosteric pocket and are active against this mutation, with high selectivity over wild-type EGFR. The most potent examples we developed from that series have a potential chemical instability risk from the combination of the amide and phenol groups. We explored a scaffold hopping approach to identify new series of allosteric EGFR inhibitors that retained good potency in the absence of the phenol group. The 5-F quinazolinone 34 demonstrated tumor regression in an H1975 efficacy model upon once daily oral dosing at 25 mg/kg.
Identifiants
pubmed: 35378251
pii: S0960-894X(22)00194-9
doi: 10.1016/j.bmcl.2022.128718
pmc: PMC9749896
mid: NIHMS1852250
pii:
doi:
Substances chimiques
Phenols
0
Protein Kinase Inhibitors
0
Quinazolinones
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
128718Subventions
Organisme : NIGMS NIH HHS
ID : P41 GM103403
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA154303
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA247198
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA201049
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM124165
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
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