BH3-only蛋白和自噬相关蛋白的表观和非表观遗传修饰及BH3拟似药的研究

BH3拟似药通过模拟BH3-only蛋白促进肿瘤细胞凋亡和调节自噬，是肿瘤治疗中最具前景的药物之一。BH3-only蛋白是BCL-2家族的促凋亡成员，可与抗凋亡成员结合启动肿瘤细胞凋亡和自噬。我们前期采用虚拟筛选和分子对接从31万余种化合物中筛选发现天然产物单体AD21和AD23是潜在的BH3拟似药，初步研究发现它们对非小细胞和小细胞肺癌有抑制作用，另有报道表明含有它们的混合物可抑制HDAC。本项目将确认这两个化合物与BCL-2多种抗凋亡成员的结合及对肺癌的抑制作用；它们抑制HDAC的活性及对BH3-only蛋白和自噬相关蛋白的表观和非表观遗传修饰，进而抑制Beclin1与BCL-2复合物形成，并调节PI3K-AKT-mTOR和FOXO1/SIRT1/Atg7通路及扩展的网络。为阐明BH3-only蛋白在肿瘤进展中的角色，及AD21和AD23的作用机制，发展新的BH3拟似药奠定基础。

BH3 mimetics are small molecules designed to mimic the binding of BH3-only proteins to the hydrophobic groove of antiapoptotic BCL2 proteins. BH3 mimetics can activate the both of apoptosis and autophagy in tumor cells and now it is one of the most promising therapy for cancers. As a pro-apoptotic member of the BCL-2 family, the dysfunction of BH3-only protein will lead to the tumor progression. We previously employed virtual screening technique to screen from 140,000 of synthetic compounds and 170,000 of natural products libraries and found that there two pure natural compounds of AD21 and AD23 are potential BH3-mimetics candidates. Their mixtures have been reported to have the inhibitory effects on histone deacetylase (HDAC). Our preliminary study also showed that the both compounds could dramatically inhibit the growth of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells. Molecular docking technology implied the both can binding to variety BH3-only proteins. . The proposed project will further determine the effects of these two compounds on both NSCLC and SCLC growth and metastasis. Confirming the bindings of these two compound to the hydrophobic groove of antiapoptotic BCL2 family members. Clarifying their ability of inhibition on HDAC and their epigenetic and non-epigenetic modifications on BH3-only proteins and autophagic related proteins after treatment. Elucidating the formation of Beclin1 and BCL-2 complexes and the signal pathways of PI3K-AKT-mTOR and FOXO1/Sirt1/Atg7 by which the cell apoptosis and autophagy were induced after administrations. Finally by using proteomic and network analysis technologies to construct the extended regulation networks and identifying new key node by the two compounds. Based on above proposed studies, we hope to provide evidences for illustrating the role of BH3-only protein in lung cancer progression, and facilitate the discovery of new BH3-mimetic drugs.