Article
Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC.
Bioorganic & medicinal chemistry letters - 15 Jul 2022
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
Abstract excerpt
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...
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