Synthesis and biological evaluation of irreversible EGFR tyrosine kinase inhibitors containing pyrido[3,4-d]pyrimidine scaffold |
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Authors: | Hao Zhang Jin Wang Hong-Yi Zhao Xue-Yan Yang Hao Lei Minhang Xin Yong-Xiao Cao San-Qi Zhang |
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Institution: | 1. Department of Medicinal Chemistry, School of Pharmacy, Xi′an Jiaotong University, Xi′an, Shaanxi 710061, PR China;2. Department of Pharmacology, School of Basic Medical Science, Xi′an Jiaotong University, Xi′an, Shaanxi 710061, PR China |
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Abstract: | In the present study, a new class of compounds containing pyrido3,4-d]pyrimidine scaffold with an acrylamide moiety was designed as irreversible EGFR-TKIs to overcome acquired EGFR-T790M resistance. The most promising compound 25h inhibited HCC827 and H1975 cells growth with the IC50 values of 0.025?μM and 0.49?μM, respectively. Meanwhile, 25h displayed potent inhibitory activity against the EGFRL858R (IC50?=?1.7?nM) and EGFRL858R/T790M (IC50?=?23.3?nM). 25h could suppress EGFR phosphorylation in HCC827 and H1975 cell lines and significantly induce the apoptosis of HCC827 cells. Additionally, compound 25h could remarkably inhibit cancer growth in established HCC827 xenograft mouse model at 50?mg/kg in vivo. These results indicated that the 2,4-disubstituted 6-(5-substituted pyridin-2-amino)pyrido3,4-d]pyrimidine derivatives can serve as effective EGFR inhibitors and potent anticancer agents. |
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Keywords: | EGFR-TKIs Anticancer Irreversible inhibitors Drug design |
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