各代EGFR-TKIs是目前临床上最活跃最重要的一线靶向治疗肿瘤药物，但用药一段时间均出现耐药。EGFR上L718Q和T790M位点突变是目前公认的产生第三代EGFR-TKIs临床上耐药的主要位置，因此寻找新的克服第三代EGFR-TKIs耐药的小分子化合物是目前肿瘤药物研究最前沿最热点的问题。前期结合多种策略发现两株软珊瑚真菌具有独特代谢途径，次生代谢产物丰富；新颖色酮多聚体和叶立德类成分明显具有克服第三代EGFR-TKIs耐药活性，且与L718Q和T790M位点突变相关。本项目拟在EGFR L718Q/T790M靶点指导下，结合HPLC、GNPS和NMR技术对含有新颖骨架化合物部位进行分离鉴定，并对其进行克服肿瘤耐药活性测试及可能机理和构效关系研究，旨在发现具有克服肿瘤耐药活性的先导物，为新模式下从海洋环境中发现高效广谱克服第三代EGFR-TKIs耐药的小分子抑制剂提供科学依据。

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are one of the most efficient and significant drugs for tumor treatment in the clinic. However more and more clinical symptoms showed it is very easy to induce drug resistance of tumor cells by EGFR-TKIs, and is very hard to inhibit regeneration of tumor after a period of usage of EGFR-TKIs. T790M and L718Q resistance mutations of EGFR are universally accepted by most tumor researchers. So it is the hot topic to look for novel molecular-targeting agents to overcome multdrug resistance of tumor induced by EGFR TKIs. . Results of our previous research showed that two soft coral-derived fungus had particular metabolic pathways and a variety of structures of secondary metabolites by strage of OSMAC (one strain many compounds) and detection of HPLC, GNPS (Global Natural Products Social Molecular Networking), HPLC, and NMR meanwhile novel Ylides and chromones were significant activities against tumor drug resistance cell lines induced by EGFR-TKIs. . This project goes on for isolation, purification, and identification of secondary metabolites from subfractions contained novel compounds according to the singals of GNPS, further illumination the mechanism and structure-activity relationship by the calculation of quantum chemistry. Certainly, this project aims to discover the significant efficient and broad inhibitors against drug resistance of tumor cells induced EGFR-TKIs..