Abstract

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 CF₂-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.

Graphic abstract

摘要

受体酪氨酸激酶 c-Met 是重要的抗肿瘤药物靶点。三唑并三嗪类似物2 – 10得到了有效制备，并评估了酶促和细胞 c-Met 活性。研究了三唑并三嗪核心和 CF _{2 -}喹啉部分的简要构效关系，从而发现了具有纳摩尔酶促 c-Met 活性和亚纳摩尔 MKN45 和 EBC-1 细胞效力的化合物8。提出的8和 c-Met 的结合模型揭示了两个典型的氢键和一个π – π 抑制剂与 c-Met 激酶结构域的 ATP 结合位点之间形成堆积相互作用，这解释了其有效的 c-Met 活性。

图形摘要