Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC

Autor:	Thomas W. Gero, David E. Heppner, Tyler S. Beyett, Ciric To, Seth C. Azevedo, Jaebong Jang, Thomas Bunnell, Frederic Feru, Zhengnian Li, Bo Hee Shin, Kara M. Soroko, Prafulla C. Gokhale, Nathanael S. Gray, Pasi A. Jänne, Michael J. Eck, David A. Scott
Rok vydání:	2021
Předmět:	Lung Neoplasms Organic Chemistry Clinical Biochemistry Pharmaceutical Science Biochemistry ErbB Receptors Phenols Drug Resistance Neoplasm Carcinoma Non-Small-Cell Lung Cell Line Tumor Drug Discovery Mutation Molecular Medicine Humans Molecular Biology Protein Kinase Inhibitors Quinazolinones
Zdroj:	Bioorganicmedicinal chemistry letters. 68
ISSN:	1464-3405
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f1bfb1415ffe44876f18b0e35b149a21 https://pubmed.ncbi.nlm.nih.gov/35378251 Zobrazit plný text záznamu Full Text from ScienceDirect