ROS1酪氨酸激酶与癌基因融合形成的融合蛋白是治疗非小细胞肺癌等肿瘤的有效分子靶点，但激酶结构域突变是引起耐药并导致治疗失败的主要原因。目前已知的ROS1抑制剂是兼有ROS1抑制活性的多靶点酪氨酸激酶抑制剂，国内尚无ROS1抑制剂报道。因此，急需发现新的高选择性ROS1抑制剂用于ROS1异常和突变耐药性肿瘤的治疗。我们前期设计合成了系列c-Met/ALK抑制剂，并发现化合物SMU-B具有很强的ROS1抑制活性。本项目拟以SMU-B为先导化合物，通过分子对接、分子动力学模拟、3D-QSAR等方法，首次设计和合成系列结构新颖的选择性ROS1Ⅰ型抑制剂和以新的“DFG-shefited”构象结合的Ⅱ型抑制剂；并通过测定抑制ROS1生化和细胞激酶的磷酸化，测定融合蛋白激酶区突变耐药细胞的磷酸化以及耐药细胞存活来评价化合物活性；旨在发现高选择性和抗激酶区突变耐药的ROS1抑制剂。

ROS1-oncogene fusion proteins are effective molecular targets for anaplastic lymphoma kinase inhibitor in non-small celll lung cancers, but the mutations in kinase domain of ALK-oncogene fusion proteins are responsible for ALK inhibitor resistance in these cancers.At present, only multiple receptor tyrosine kinase inhibitor with ROS1 inhibitory activity are reported overseas, and no ROS1 inhibitors are found in China. Therefore, it is necessary to find new highly selective ROS1 inhibitors for treatment of patients with abnormal ROS1 activity and anti-ALK drug resistance. In our previous study, we designed and synthesized series of inhibitors of c-Met/ALK, and found that the compound SMU-B had strong ROS1 inhibitory activity. In this study, based on the structure of a lead compound SMU-B, we design and synthesize a series of novel type I and type II inhibitors with a new "DFG-shefited" conformation binding, by using of molecular docking, molecular dynamics simulation and 3D-QSAR. We measure ROS1 kinase phosphorylation,cell fusion protein kinase phosphorylation, and the cell growth activity to determine the biological activity of these compounds. The purpose of our study is to find new drugs with high selectivity and activity of anti-ALK drug resistance induced by kinase domain mutation of ROS1.