Class II型多靶点c-Met激酶抑制剂的分子构建和抗肿瘤活性研究

c-Met kinase belongs to a subfamily of RTKs，and it plays an important role in the HGF/c-Met signaling cascade. c-Met kinase is critical to the survival, growth and proliferation of cells. Overexpression of c-Met kinase is found in several tumor types, and has become an attractive target in cancer therapy. Cabozantinib, a marketed multikinase inhibitor against c-Met, VEGFR and Ret, demonstrates outstanding inhibitions across a broad spectrum of tumor types. However, its unsatisfactory bioavailability and adverse effects which are accompanied with the poor water-solubility limit the application to some extent. In previous studies, we found several Class II multi-target c-Met kinase inhibitors bearing aromatic heterocyclic containing pyridine as the hinge-region binder, such as D-196 and D-25, which had satisfactory water-solubility and demonstrated better antitumor potency than cabozantinib in several cancer cells. In this research, we serve aromatic heterocyclic containing pyridine as a privileged fragment for the hinge-region binder, and introduce groups with high water-solubility. Further structure modification will be carried out on the hydrogen bond binding region to discover novel Class II multi-target c-Met kinase inhibitors, which possess good activity, safety as well as pharmacokinetic properties.

c-Met激酶是受体酪氨酸家族（RTKs）中的一员，在HGF/c-Met信号传导通路中发挥着重要作用，其过表达会导致细胞的过度增殖，已被确认为肿瘤治疗的重要靶点。上市药物Cabozantinib具有广谱的抗肿瘤活性，但由于其分子水溶性小、生物利用度低、毒副作用较多，限制了其临床应用。前期研究中，本课题组发现了D-196和D-25等多个含吡啶结构的芳香杂环片段作为铰链区结合位点的Class II型多靶点c-Met激酶抑制剂，其对肿瘤细胞的增殖抑制作用明显优于Cabozantinib，而且具有良好的水溶性。本课题拟将含吡啶结构的芳香杂环作为铰链区结合位点的骨架结构开展深入的优化设计，引入水溶性较强的侧基，寻找更佳的铰链区结合位点结构，并进一步对氢键结合区进行结构修饰，从而获得新的具有良好生物活性、成药性的Class II型多靶点c-Met激酶抑制剂。

c-Met激酶作为肿瘤细胞信号转导通路中的关键节点蛋白，在肿瘤细胞生长、增值、侵袭和转移等过程中发挥着重要作用，开发基于c-Met激酶的小分子抑制剂已成为抗肿瘤靶向治疗药物研究热点之一。在本项目前期研究工作中，已发现了D-196和D-25等多个多靶点c-Met激酶抑制剂，其对肿瘤细胞的增殖抑制作用明显优于Cabozantinib，并结合已报道的II型多靶点c-Met激酶抑制剂的结构特点，构建了其药效团模型：其分子结构可分为铰链区结合位点（HRB）、链接臂(Linker)、氢键结合区（HBR）和疏水片段（HM）。本项目以Cabozantinib、Foretinib、Golvatinib等为先导化合物，主要在HBR区开展了结构优化设计，引入了具有单环结构的哒嗪酮和三氮唑片段，同时引入了具有双环结构喹啉酮、1,8-萘啶-2-酮和1,8-萘啶-4-酮片段，设计新型多靶点c-Met激酶抑制剂。通过化学合成、生物活性筛选等手段，开发体内外活性及成药性优异的新型多靶点c-Met激酶抑制剂。