Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
Department of Pharmacology, School of Basic Medical Science, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
Bioorg Med Chem. 2018 Jul 23;26(12):3619-3633. doi: 10.1016/j.bmc.2018.05.039. Epub 2018 May 24.
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 IC values of 0.025 μM and 0.49 μM, respectively. Meanwhile, 25h displayed potent inhibitory activity against the EGFR (IC = 1.7 nM) and EGFR (IC = 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.
在本研究中，设计了一类含有吡啶并[3,4-d]嘧啶骨架和丙烯酰胺部分的新型化合物，作为克服获得性 EGFR-T790M 耐药性的不可逆 EGFR-TKIs。最有前途的化合物 25h 对 HCC827 和 H1975 细胞的生长具有抑制作用，IC 值分别为 0.025μM 和 0.49μM。同时，25h 对 EGFR（IC=1.7nM）和 EGFR（IC=23.3nM）具有很强的抑制活性。25h 能抑制 HCC827 和 H1975 细胞系中 EGFR 的磷酸化，并显著诱导 HCC827 细胞的凋亡。此外，化合物 25h 在体内以 50mg/kg 的剂量能显著抑制已建立的 HCC827 异种移植小鼠模型中的肿瘤生长。这些结果表明，2,4-二取代的 6-(5-取代吡啶-2-氨基)吡啶并[3,4-d]嘧啶衍生物可以作为有效的 EGFR 抑制剂和有效的抗癌剂。
