Discoveryof selectiveEGFRmodulatortoinhibitL858R/T790M doublemutantsbearingaN-9-Diphenyl-9H-purin-2-aminescaffold

Publication date: Available online 17 February 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Jinxing Hu, Yufei Han, Jingtao Wang, Yue Liu, Yanfang Zhao, Yajing Liu, Ping Gong
Based upon the modeling binding mode of marketed AZD9291 with T790M, a series of N-9-Diphenyl-9H-purin-2-aminederivatives were designed and synthesized with the purpose to overcome the drug resistance resulted from T790M/L858R double mutations. The most potent compound 23a showed excellent enzyme inhibitory activities and selectivity with nanomolar IC50 values for both the single T790M and double T790M/L858R mutant EGFRs, and was more than 8-fold selective for wild type EGFR. Compound 23a displayed strong antiproliferative activity against the H1975 non-small cell lung cancer (NSCLC) cells bearing T790M/L858R. And it was less potent against A549 (WT EGFR and k-Ras mutation) and HT-29 (non-special gene type) cells, showing a high safety index.

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