新型抗耐药ALK抑制剂的分子设计及药理活性初步评价

ALK is the most efficient drug target for the therapy of fusion-type NLCLC. However, with the occurrence of drug resistance mutations, most launched drugs, such as crizotinib, ceritinib, and alectinib, become inefficient to the mutated target (especially the G1202R and T1151ins mutants). Therefore, an opening problem comes up to us is the design and development of novel anti-resistance ALK drugs to combat the drug resistance caused by the mutations. . It is well-known that the occurrence of drug resistance mutations can seriously affect the drugs binding and thereafter leads to drug resistance. Considering the fact that mutations with different locations will result in different drug resistance mechanisms to the drugs, which may affect the drugs residence time, binding channel, and induced fit effect, etc., it is necessary to use multiple free energy calculation methods to analyze the drug resistance mechanism. Therefore, herein, we will use multiple free energy calculation strategy (namely hierarchical drug resistance analysis strategy) to filter and evaluate the anti-resistance effect of the potential ALK inhibitors (here, the G1202R and T1151ins mutants will be used for the design of ALK inhibitors to combat drug resistance). Besides, we will use various experimental methods to test the selected compounds for the purpose of finding several ALK inhibitors with novel structure, strong specificity, and high inhibitory activity.

间变性淋巴瘤激酶ALK是最为有效的融合型非小细胞肺癌治疗靶标，然而，随着ALK中大量耐药性突变的出现，其对现有上市药物（如crizotinib、ceritinib、alectinib）均产生不同程度的耐药性（其中G1202R和T1151ins突变的耐药性尤为强烈）。因此，针对ALK激酶的抗耐药抑制剂设计已成为当下亟待解决的问题。研究表明，药物靶标中耐药性位点的出现会严重影响药物与靶标的结合。根据突变位置的不同，其可能影响到药物-靶标相互作用的任何一步（如对保留时间的影响、结合通道的影响、诱导契合效应的影响等）。因此，本项目拟从多维度自由能计算角度出发，通过高精度分类模型的构建和层级式抗耐药能力评估来筛选潜在ALK抗耐药抑制剂（拟对ALK的G1202R和T1151ins突变体开展工作），并通过联合多种实验手段，力争发现数个结构新颖、专一性效果好、抑制活性强的ALK抗耐药先导化合物。

项目针对ALK抗耐药抑制剂进行合理设计，通过创新算法研究，发现数个活性较好ALK抗耐药抑制剂，其中最好抑制剂活性达到174 pM，并在多个ALK耐药突变体中展现良好活性，以及具有良好激酶靶点选择性，该项目为ALK融合型非小细胞肺癌的抗耐药治疗带来了曙光。