Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC. (15th July 2022)

• Record Type: Journal Article
• Authors: Gero, Thomas W.; Heppner, David E.; Beyett, Tyler S.; To, Ciric; Azevedo, Seth C.; Jang, Jaebong; Bunnell, Thomas; Feru, Frederic; Li, Zhengnian; Shin, Bo Hee; Soroko, Kara M.; Gokhale, Prafulla C.; Gray, Nathanael S.; Jänne, Pasi A.; Eck, Michael J.; Scott, David A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 68(2022)
• Publication Date: 2022-07-15
• Subjects: EGFR -- Allosteric inhibitor -- Kinase inhibitor -- Quinazolinone -- Non-small cell lung cancer; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128718
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.