成纤维生长因子受体(FGFR)与多种肿瘤的发生、发展密切相关，FGFR抑制剂的研发已成为抗肿瘤药物研究的热点，但当前该类抑制剂已存在耐药性问题，全面阐释FGFR抑制剂的耐药机制，并针对性进行药物设计是目前面临的瓶颈和急需解决的关键科学问题。FGFR中ATP结合区的“卡口”残基突变是产生耐药性的重要原因。本项目拟针对该耐药机制，对前期发现的吲唑类先导化合物C29进行结构优化，同时基于片段生长的策略引入丙烯酰胺弹头，实现与靶蛋白中的Cys共价结合，设计合列系列新骨架化合物。深入评价相关化合物的体外活性，获得的优选化合物联合PET-CT影像技术进行体内活性评价，最终发现新型共价不可逆、抗耐药的FGFR抑制剂，并以此为契机探索FGFR抑制剂的耐药机制，从而为发展机制新颖、成药性好具有自主知识产权的抗肿瘤新药奠定基础。

Fibroblast growth factor receptor (FGFR), which is closely related to the occurrence and development of various tumors, serves as a critical target for cancer and the development of FGFR inhibitor has emerged as a hot area for antitumor drugs study. However, the resistance to monotherapy with FGFR inhibitors caused the bottleneck for the development of new generation of FGFR inhibitors by deciphering and overcoming the underlying mechanism of resistance. The key factor of FGFR inhibitor resistance is related to “gatekeeper” residue mutation which located in the ATP-binding pocket. This project is target on “gatekeeper” residue mutation and using fragment-based strategies design, synthesis and biological evaluation of novel FGFR inhibitors that bearing an indazole scaffold , with addition of introducing of acrylamide warhead that undergoes Michael addition reaction with cysteine residue in the ATP-binding pocket. Subsequently evaluate for their in vivo activity using Positron Emission Tomography Computed Tomography (PET-CT). As a result, this project will not only focus on the mechanism of drug resistance, but also to open a new avenue for the development of novel covalent and irreversible FGFR inhibitors which overcoming the resistance to first-generation FGFR inhibitors.