肺组织靶向性微管抑制剂SKLB060肺部特异性靶点鉴定

Lung cancer has become the leading cause of cancer death. However,conventional lung cancer therapies (chemotherapeutics and targeted drugs) lack lung tissue targeting ability and these drugs show obvious side effects on other tissues. Increasing the tissue targeting of lung cancer drugs is an effective way to increase the curative effect and reduce the side effects of the drugs. However, achieving lung tissue targeting of these drugs is a feasible but difficult goal. So far, there are few small molecule drugs that have both therapeutic effect and lung tissue targeting ability. This makes our lung tissue targeting tubulin inhibitor SKLB060 have good research and drug-development value. Our previous studies found that the tubulin inhibitor SKLB060 can directly target the lung tissue, and has small toxicity and large therapeutic window (about 20), while other tubulin inhibitors lack lung tissue targeting ability. All these implied that SKLB060 has other specific target on lung tissues. Therefore, our study intends to use SPR surface plasmon resonance technology, biotin labeled fishing target technology, small molecules and protein co-crystallization technology to (1) confirm the lung specific target protein of SKLB060 (2) to investigate the interaction between SKLB060 and targeted protein. (3) verify that the targeted protein does indeed achieve lung-specific targeting.

肺癌已经成为癌症死亡的第一原因，但传统的肺癌治疗药物（化疗药物及靶向药物）缺乏肺组织靶向性。对肺以外的其他组织具有较明显的副作用。增加肺癌药物的组织靶向性是增加药物的疗效和减低副作用的有效手段，但药物的组织靶向性是可行却又难以实现的目标。目前为止，还鲜有小分子药物能够在具备治疗效果的同时还具有组织靶向性。这就使我们的肺组织靶向性微管抑制剂SKLB060具有很好的研究及开发价值。前期研究发现微管抑制剂SKLB060有明显的肺组织靶向性，且毒性小，治疗窗口大（约20）。而其他微管抑制剂缺乏肺组织靶向性。说明SKLB060除了微管蛋白的靶点以外，还有在肺部的其他特异性靶点。因此，本课题拟采用SPR 表面等离子共振技术，生物素标记钓靶点技术，小分子与蛋白共结晶技术等（1）鉴定SKLB060肺部的特异性靶蛋白。（2）考察SKLB060与靶蛋白的相互作用。（3）验证该靶蛋白能实现肺部靶向性。

肺癌已经成为癌症死亡的第一原因，但传统的肺癌治疗药物（化疗药物及靶向药物）缺乏肺组织靶向性。对肺以外的其他组织具有较明显的副作用。增加肺癌药物的组织靶向性是增加药物的疗效和减低副作用的有效手段，但药物的组织靶向性是可行却又难以实现的目标。目前为止，还鲜有小分子药物能够在具备治疗效果的同时还具有组织靶向性。这就使我们的肺组织靶向性微管抑制剂SKLB060具有很好的研究及开发价值。前期研究发现 微管抑制剂SKLB060有明显的肺组织靶向性，且毒性小，治疗窗口大（约20）。而其他微管抑制剂缺乏肺组织靶向性。说明SKLB060除了微管蛋白的靶点以外，还有在肺部的其他特异性靶点。本项目采用了两种方法确定SKLB060的靶点为laminin，并通过MST实验进行了确证。同时，优化合成了SKLB060的衍生物，考察了其抗肿瘤效果等工作，发表相关SCI论文5篇，10分以上一篇。基本完成了既定目标。

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