由EGFR突变导致的耐药问题是非小细胞肺癌(NSCLC)靶向药物临床应用的一大瓶颈和亟待解决的难题。传统的小分子抑制策略已无法彻底解决耐药问题，因此寻求全新的药物研发策略已成为基础和临床研究的热点。蛋白靶向降解嵌合小分子(PROTAC)技术能将靶蛋白和泛素连接酶E3拉近，从而利用细胞固有的泛素-蛋白酶体系统将靶蛋白降解，已经成为目前开发靶向药物的新思路，并开始从基础研究向临床应用发展。.PROTAC是一个双功能嵌合分子，由靶蛋白配体、连接链和E3连接酶配体组成。本项目拟以EGFR的变构位点作为其配体分子的着落点，设计并合成全新的PROTAC。探究该类PROTAC对EGFR野生型和突变型的结合、降解能力；对泛素化降解相关参与蛋白表达水平的影响；对下游关键激酶磷酸化水平的影响；对耐药细胞株的抗增殖活性，从而初步揭示该类PROTAC抗NSCLC的构效特点、规律和克服耐药机制。

Drug resistance caused by EGFR mutations is a major bottleneck and a problem to be solved in the clinical application of targeted drugs for non-small cell lung cancer (NSCLC). Traditional small-molecule inhibition strategies can not completely solved the problem of drug resistance. Therefore, seeking new drug development strategies has become the focus of basic and clinical research. Protein-targeted degradation of small molecule (PROTAC) technology can bring the target protein and ubiquitin ligase E3 closer together, thereby using the cell's inherent ubiquitin-proteasome system to degrade the target protein, which has become the new way for target drug development currently. This strategie has began to develop from basic research to clinical application..PROTAC is a bifunctional chimeric molecule consisting of a target protein ligand, a linker, and an E3 ligase ligand. This project intends to use the allosteric site of EGFR as the landing point of its ligand molecule to design and synthesize new PROTAC. Investigate the binding and degradation ability of this type of PROTAC to EGFR wild-type and mutant types; Influence on the expression level of related ubiquitin degradation-related proteins; Effect on downstream phosphorylation levels of key kinases; Anti-proliferative activity on resistant cell lines, Thus, the structure-activity characteristics, regularity of this type of PROTAC in anti-NSCLC and the mechanism of overcoming drug resistance were initially revealed.