Cui Zhishan, Chen Shaopeng, Wang Yanwei, Gao Chunmei, Chen Yuzong, Tan Chunyan, Jiang Yuyang
The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Antitumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
Eur J Med Chem. 2017 Aug 18;136:372-381. doi: 10.1016/j.ejmech.2017.05.006. Epub 2017 May 11.
Overexpression of EGFR is often associated with advanced stage disease and poor prognosis. In certain cancers, Src works synergistically with EGFR to promote proliferation, survival, invasion and metastasis. Development of dual-target drugs against EGFR and Src is of therapeutic advantage against these cancers. Based on molecular docking and our previous studies, we rationally designed a new series of azaacridine derivatives as potent EGFR and Src dual inhibitors. Most of the synthesized azaacridines displayed good antiproliferative activity against K562 and A549 cells. The representative compound 13b showed nM IC values against K562 and A549 cells, and inhibited EGFR at inhibition rate of 33.53% at 10 μM and Src at inhibition rate of 72.12% at 1 μM. Furthermore, compound 13b could inhibit the expression of EGFR, p-EGFR, Src and p-Src. Moreover, 13b efficiently inhibited the invasion of tumor cells and induced cancer cells apoptosis. Our study suggested that azaacridine scaffold can be developed as novel multi-target kinase inhibitors for cancer therapy.
表皮生长因子受体（EGFR）的过表达通常与晚期疾病和不良预后相关。在某些癌症中，Src与EGFR协同作用，促进细胞增殖、存活、侵袭和转移。开发针对EGFR和Src的双靶点药物对这些癌症具有治疗优势。基于分子对接和我们之前的研究，我们合理设计了一系列新型氮杂吖啶衍生物作为有效的EGFR和Src双抑制剂。大多数合成的氮杂吖啶对K562和A549细胞显示出良好的抗增殖活性。代表性化合物13b对K562和A549细胞的IC值为纳摩尔级别，在10μM时对EGFR的抑制率为33.53%，在1μM时对Src的抑制率为72.12%。此外，化合物13b可以抑制EGFR、磷酸化EGFR（p-EGFR）、Src和磷酸化Src（p-Src）的表达。而且，13b能有效抑制肿瘤细胞的侵袭并诱导癌细胞凋亡。我们的研究表明，氮杂吖啶骨架可开发为用于癌症治疗的新型多靶点激酶抑制剂。
