烟酰胺磷酸核糖转移酶是一个治疗肿瘤的全新靶点。阻断烟酰胺磷酸核糖转移酶可以有效抑制肿瘤的生长和转移。本项目利用以计算机辅助药物设计的方法成功设计合成了一系列全新的烟酰胺磷酸核糖转移酶抑制剂，其中化合物30具有很好的烟酰胺磷酸核糖转移酶抑制活性。进一步体内与体外实验表明它能够有效抑制肿瘤的生长。化合物30是二期临床药物FK866的的5倍左右，是潜在的优良的抗癌药物。在此基础上，运用X晶体衍射技术阐明它们与烟酰胺磷酸核糖转移酶的相互作用特征，然后采用基于片段的设计方法组装和合成新的高效烟酰胺磷酸核糖转移酶抑制剂。选择其中的一个或者多个化合物，把它们当作分子探针，探索烟酰胺磷酸核糖转移酶在肿瘤病理过程中起的作用。本课题还将为开发新型的烟酰胺磷酸核糖转移酶抑制剂抗肿瘤药物提供重要的候选药物。

Nicotinamide phosphoribosyltransferase (Nampt) is new target for cancer therapy. Inhibition of Nampt could potentially modulate tumor genesis and metastas in vivo. By using molecular modeling of FK866 with Nampt, we designed and synthesized novel Nampt inhibitors. Among them, compound 30 demonstrates very potent binding affinity to Nampt. Further biological studies show that compound 30 can inhibit the growth of tumor efficiently both in vitro and in vivo. Most importantly, compound 30 show much 5-fold more activities against MDA-MB-231 than FK866, which is in phase II. The binding of several selective Nampt inhibitors to the target of Nampt will be determined by biophysics methods such as X-ray crystallography technique. Moreover, fragment-based drug design methods also will be employed to design novel and potent Nampt inhibitors. One or few compounds gotten by these methods will be used as probes for future studies of this therapeutic avenue toward the potential treatment of cancer. This project will provide the new therapeutic agents as anti-cancer drugs for targeting Nampt.