2型糖尿病(T2DM)主要是由胰岛素抵抗或胰岛素分泌相对不足引起的代谢综合症，通过调控糖异生途径抑制肝糖异生过程以降低血糖是治疗T2DM的重要策略。TORC2是调节肝糖异生途径重要的转录辅因子，它主要辅助环腺苷酸反应元件结合蛋白(CREB)对共激活因子的招募及促进含有CRE元件的基因表达，对肝葡萄糖产生起关键调节作用。因此，TORC2靶向调节剂将为抗T2DM药物研发提供了新的研究思路。目前通过靶向TORC2来抑制肝糖异生改善机体糖稳态的小分子发现研究在国际上还处于起步阶段，鲜有重要成果报道。本项目将基于已有工作基础，以发现抗T2DM药物先导结构的科学问题为主要研究对象，加强药理学、计算生物学和药物化学等学科交叉融合，针对调节糖异生关键蛋白TORC2调控机制，开展TORC2靶向调节剂的发现研究，建立抗T2DM药物设计新体系，获得有前景的抗T2DM药物先导物，培养高水平药物设计研究复合型人才。

Type 2 diabetes mellitus (T2DM) is a metabolic syndrome mainly caused by insulin resistance and/or relatively insufficient insulin secretion. It is a promising therapeutic strategy against T2DM to improve hyperglycaemia by inhibition of gluconeogenesis in the liver through regulating the relevant pathways. TORC2 as a key transcription cofactor functions potently in the regulation of the gluconeogenesis-involved signaling. It assists the coactivator recruitment for cAMP response element-binding protein (CREB) and stimulates the expression of CRE element genes, thus playing a crucial regulatory role in hepatic glucose production. Therefore, TORC2 targeted regulator may supply new idea for anti-T2DM drug discovery. Currently, the research in the discovery of the TORC2 targeted small molecules able to ameliorate glucose homeostasis through inhibiting liver gluconeogenesis is still in its beginning stage, and no sound results have yet reported in this field. In this project, we will focus on the major scientific topics involved in the innovative anti-T2DM drug lead compound discovery,perform the research in discovering TORC2 targeted regulator through investigation of TORC2 regulation mechanisms based on our previously achieved results and the multi-discipline integration of the advanced technologies in pharmacology, computational biology and medicinal chemistry, set up new anti-T2DM design system, obtain promising anti-T2DM drug lead compounds and foster advanced inter-disciplinary talents in drug design.