Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai, 201203, China.
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
Mol Divers. 2021 May;25(2):839-846. doi: 10.1007/s11030-020-10067-5. Epub 2020 Mar 10.
Receptor tyrosine kinase c-Met is an important antitumor drug target. Triazolotriazine analogues 2-10 were prepared efficiently and evaluated the enzymatic and cellular c-Met activities. Brief structure-activity relationships of triazolotriazine core and CF-quinoline part were investigated, leading to the discovery of compound 8 with nanomolar enzymatic c-Met activity, and subnanomolar MKN45 and EBC-1 cellular potencies. The proposed binding model of 8 and c-Met unraveled that two canonical hydrogen bonds and a π-π stacking interaction formed between the inhibitor and the ATP binding site of c-Met kinase domain, which accounted for its potent c-Met activities.
受体酪氨酸激酶 c-Met 是一个重要的抗肿瘤药物靶点。我们高效地合成了三唑并三嗪类似物 2-10，并评估了它们对酶和细胞 c-Met 活性的抑制作用。我们对三唑并三嗪核心和 CF-喹啉部分的结构-活性关系进行了简要研究，发现化合物 8 具有纳摩尔级别的酶 c-Met 活性，对 MKN45 和 EBC-1 细胞的抑制活性达到亚纳摩尔级。8 与 c-Met 的结合模型表明，抑制剂与 c-Met 激酶结构域的 ATP 结合位点之间形成了两个典型的氢键和一个 π-π 堆积相互作用，这解释了其对 c-Met 的高效抑制活性。
