Design of Potent and Selective EGFR Inhibitors against L858R/T790M Resistance Mutation

Through a 3D conformer based scaffold hopping protocol based on previously reported mutant-selective EGFR inhibitorswe designed and synthesized a series of pyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione derivatives as novel potent and selective EGFRL858R/T790M inhibitors. For three compounds (20b20c and 20g) in this series, our design strategy to occupy S2 pocket boosts the inhibitions against double-mutant EGFR and brings the IC50 to a subnanomolar level. After three round SAR explorations, one of the most promising compounds 20g shows a favorable selectivity at both in vitro and in vivo levels, indicating that compound 20g might be used as a promising drug candidate to overcome EGFRL858R/T790M drug-resistance mutation. Further evaluation for the candidate compound is still ongoing, and will be reported in due course.


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Shanghai Key Laboratory of New Drug Design
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East China University of Sci. & Tech.
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