靶向cSH2结构域的新型PLCγ1选择性抑制剂设计、合成及其缓解FGF23诱导心室重构的药理作用研究

近年发现，FGF23是多种因素导致的心室重构和心力衰竭的重要病理诱导因子，通过FGF23-FGFR4-PLCγ1信号发挥诱导心室重构的作用。因此，PLCγ1成为治疗FGF23相关心衰疾病的重要靶点。目前尚无特异性抑制FGF23病理信号的PLCγ1抑制剂报道。课题组前期以同源蛋白二聚化结构为模板，构建了FGFR4 KD-PLCγ1 cSH2二聚化模型，并认为二聚化模型中的结合口袋可能是研发新型抑制剂的潜在作用位点。我们经过虚拟筛选已经获得靶向抑制PLCγ1 cSH2结构域的噻唑酮类先导化合物AN698。本项目将进一步设计、合成不同系列的噻唑酮类衍生物，考察它们对PLCγ1 cSH2的结合能力、抑制活性和选择性，并利用细胞和动物模型评价抑制剂对FGF23诱导的心室重构的治疗作用，通过结构生物学阐明抑制剂与cSH2的结合机制。本研究将为FGF23相关心脏疾病防治药物的设计提供新的靶点和先导结构。

Cardiovascular diseases are the leading cause of death worldwide. Heart failure is the terminal manifestation of cardiovascular diseases, and its pathogenesis is very complicated. Ventricular remodeling is an important factor leading to the progressive development of heart failure, and alleviating ventricular remodeling can reduce the morbidity and mortality of heart failure.. In recent years, FGF23 has been found to be an important risk factor for ventricular remodeling and heart failure caused by many factors, FGF23 stimulating ventricular remodeling through FGF23-FGFR4-PLCγ1 signal pathway. Therefore, PLCγ1 has become an important target in the treatment of FGF23 related heart failure. At present, there are no PLCγ1 inhibitors that specifically inhibit the pathological signal of FGF23. In our previous work, we constructed a dimerization model of FGFR4 KD-PLCγ1 cSH2 by using dimerization structure of their homologous protein as the template. We hypothesized that the binding pocket observed from the dimerization model might be the potential targeting site for the development of novel inhibitors. Through virtual screening, AN-698, a thiazolone derivative, has been obtained as the leading compound which targeting PLCγ1 cSH2 domain. In the current project, we will further design and synthesize different series of thiazolone derivatives, and investigate their binding ability, inhibitory activity and selectivity towards PLCγ1 cSH2 through cell and cell free study, and evaluate the therapeutic effect of inhibitors for FGF23 induced ventricular remodeling via in vivo and in vitro models, and clarify the mechanism of inhibitors binding to PLCγ1 cSH2 by using structural biology. . This study will provide a new target and lead structure for the design of FGF23 related heart disease drugs.