Structure-Guided Design of Potent and Mutant-Selective EGFR L858R/T790M Inhibitors

Through structure-guided design approach based on our previous work on mutant-selective EGFR inhibitor (compound 9), we have designed and generated a novel 1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-2-one scaffold, followed by introduction of alkyl groups contacting the Met790 gatekeeper residue into the C4-position to keep the selectivity for the EGFRL858R/T790M over EGFRWTleading to discovery of one of the most potent compound 20a20a not only showed remarkable selectivity of enzyme inhibition for EGFRL858R/T790M over EGFRWT, but also strongly inhibited the proliferation of H1975 cellswhile significantly less effective on A431 cell lines. A further preliminary in vivo antitumor efficacy evaluation on 20a suggested that it significantly inhibited tumor growth in H1975 NSCLC xenograft mouse model via po dosing at 50 mg/kg/day for 14 days. Considering the encouraging enzymatic and cellular selectivity and in vivo antitumor efficiency of compound 20athis agent might be a promising lead compound for further optimization as selective EGFRL858R/T790M inhibitor to overcome T790M resistance mutation. The results also provide more insights for designing new classes of mutant-selective EGFR inhibitors. Further pre-clinical evaluationfor the candidate compound are in progress and will be performed in due course.

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Honglin Li's Lab
Shanghai Key Laboratory of New Drug Design
School of Pharmacy
East China University of Sci. & Tech.
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Prof. Honglin Li

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