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.
Eur J Med Chem. 2018 Mar 25;148:221-237. doi: 10.1016/j.ejmech.2018.02.051. Epub 2018 Feb 16.
Targeting acquired drug resistance is the major challenge in the treatment of EGFR-driven non-small cell lung cancer (NSCLC). In this study, a novel class of compounds containing pyrido[3,4-d]pyrimidine scaffold was designed as new generation EGFR-TKIs to overcome this challenge. The most promising compound B30 inhibited HCC827 and H1975 cells growth with the IC values of 0.044 μM and 0.40 μM, respectively. Meanwhile, B30 displayed potent inhibitory activity against the EGFR (IC = 1.1 nM) and EGFR (IC = 7.2 nM). B30 could suppress EGFR phosphorylation in a dose-dependent manner in HCC827 cell line and significantly induce the apoptosis of HCC827 cells. Molecular docking indicated that the hydroxyl in B30 could form additional hydrogen bond with mutant Ser797. These findings strongly support our assumption that 2,4,6-trisubstitued pyrido[3,4-d] pyrimidine derivatives can serve as EGFR-TKIs. The predicted hydrogen bond interaction formed by a small molecule inhibitor with mutant Ser797 is available to design the fourth-generation EGFR-TKIs.
针对获得性耐药是 EGFR 驱动的非小细胞肺癌（NSCLC）治疗的主要挑战。在这项研究中，设计了一类包含吡啶并[3,4-d]嘧啶骨架的新型化合物作为新一代 EGFR-TKIs 来克服这一挑战。最有前途的化合物 B30 以 0.044 μM 和 0.40 μM 的 IC 值抑制 HCC827 和 H1975 细胞的生长。同时，B30 对 EGFR（IC=1.1 nM）和 EGFR（IC=7.2 nM）显示出很强的抑制活性。B30 能够在 HCC827 细胞系中以剂量依赖性方式抑制 EGFR 磷酸化，并显著诱导 HCC827 细胞凋亡。分子对接表明，B30 中的羟基可以与突变型 Ser797 形成额外的氢键。这些发现有力地支持了我们的假设，即 2,4,6-三取代吡啶并[3,4-d]嘧啶衍生物可以作为 EGFR-TKIs。小分子抑制剂与突变型 Ser797 形成的预测氢键相互作用可用于设计第四代 EGFR-TKIs。
