高选择性SIRT6变构抑制剂的设计、合成及抗肿瘤功能研究

SIRT6参与调控诸多生命现象，与肿瘤发生发展密切相关，起到抑癌或致癌的双重作用，其复杂的调控机制尚需深入研究。为了更好的揭示其功能机制，亟需发现SIRT6高效、高选择性抑制剂。但由于SIRT6活性中心具有高度保守性，底物竞争性抑制剂难以实现SIRT6高选择性，而变构调节剂由于靶向于不保守的变构位点，适于对蛋白家族亚型成员进行区分，有望解决SIRT6高选择性抑制的难题。我们通过自主发展的变构药物设计方法，首次发现了SIRT6变构抑制剂，具有较高的SIRTs及HDACs的选择性，体外实验显示其对白血病细胞、淋巴瘤细胞增殖具有一定的抑制活性，其作用机制尚未阐明。基于此，本项目拟：进一步提高SIRT6抑制剂的活性及选择性；阐明抑制剂与SIRT6相互作用模式；探索SIRT6抑制肿瘤的功能机制。以期为SIRT6作为抗肿瘤靶标的研究提供新依据，同时也为开发创新药物奠定先导化合物基础。

SIRT6 has been implicated in multiple biological phenomenons and associated with the genesis and development of tumors. The complex regulation mechanisms of the dual role of SIRT6 in tumor suppression or carcinogenesis need further study. In order to reveal the functional mechanisms of SIRT6 in tumors better, it is urgent to find its highly potent and selective inhibitors. However, it is difficult for the competitive inhibitors to achieve high selectivity for SIRT6 because the active site possesses high conservatism, while allosteric modulators could overcome this problems for the non-conservative allosteric sites between subtype members. We have discovered allosteric inhibitors of SIRT6 for the first time by our self-developed allosteric drug design methods, which have high selectivity for SIRTs and HDACs. It can inhibit the proliferation of leukemia cells and lymphoma cells in vitro to a certain degree, while the mechanisms have not yet been elucidated. Thus, this project intends to obtain selective SIRT6 inhibitors with high potential and illuminate their interaction mechanism as well as explore the antitumor mechanisms of SIRT6. We aimed to provide new evidence for SIRT6 as a promising antitumor drug target and contribute to innovative drug development based on the lead compound.