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Synthesis and biological evaluation of irreversible EGFR tyrosine kinase inhibitors containing pyrido[3,4-d]pyrimidine scaffold.

Abstract：

:In the present study, a new class of compounds containing pyrido[3,4-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)pyrido[3,4-d]pyrimidine derivatives can serve as effective EGFR inhibitors and potent anticancer agents.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Zhang H,Wang J,Zhao HY,Yang XY,Lei H,Xin M,Cao YX,Zhang SQ

doi

10.1016/j.bmc.2018.05.039

subject

Has Abstract

pub_date

2018-07-23 00:00:00

pages

3619-3633

issue

12

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(18)30793-4

journal_volume

26

pub_type

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