胶质瘤中HOTAIR/PRC2复合物阻断剂优选结构类似物QS0448增效EZH2抑制剂的机制研究

HOTAIR作为长链非编码RNA，其212-300nt与PRC2复合物结合并募集至细胞核、催化组蛋白H3K27的赖氨酸三甲基化修饰，抑制靶基因的表达并促进肿瘤生长。申请人前期研究发现小分子化合物AC1Q3QWB能够特异性抑制HOTAIR对PRC2的募集入核过程，从而抑制HOTAIR在胶质瘤中的功能。申请人进一步在药明康德化合物数据库中筛选并验证了活性结构QS0448。本次申请首先聚焦解析HOTAIR对NF-kB信号通路的表观遗传学调控机制；同时开展AC1Q3QWB和新的结构类似物QS0448抑瘤作用的一致性评价；在此基础上联合抑制HOTAIR转录生成（JQ1）和HOTAIR依赖的“效应器”EZH2（Tazemetostat）,对胶质瘤力求从HOTAIR生成、募集PRC2入核以及细胞核组蛋白修饰的全面阻断，为以HOTAIR/PRC2-EZH2为靶标的多靶点联合化疗奠定转化医学的基础。

Long noncoding RNAs (lincRNAs), which are dysregulated in various cancers, play a critical role in chromatin dynamics and gene regulation by interacting with key epigenetic regulators. It has been previously reported that the lincRNA HOTAIR mediates recruitment of polycomb repressive complex 2 (PRC2) leading to aberrant transcriptional silencing of tumor suppressor genes in glioma and breast cancer. The 212-300nt of HOTAIR binds to the PRC2 complex and recruits it to the nucleus, catalyzing the lysine trimethylation modification of the histone H3K27, inhibiting the expression of target genes and promoting tumor growth.Thus, lincRNA HOTAIR can serve as a promising therapeutic target. Previously, we identified a small-molecule compound AC1Q3QWB (AQB) as a selective and efficient disruptor of HOTAIR-EZH2 interaction, resulting in blocking of PRC2 recruitment and increasing tumor suppressors expression.The small molecule compound AC1Q3QWB can specifically inhibit the recruitment of PRC2 by HOTAIR, thereby inhibiting the function of HOTAIR in gliomas. Based on AC1Q3QWB, the applicant further continued to screen for the preferred structure QS0448 in WuXi PharmaTech's compound database and completed the activity verification. This present prososal will focuses on studying the epigenetic regulation mechanism of HOTAIR on the NF-kB signaling pathway.The pharmacodynamic consistency of the antitumor effect between AC1Q3QWB and the new structural analog QS0448 will be the next move. Lastly,the optimized compound will used as combined targeting therapeutics for inhibition of HOTAIR transcription generation (BRD4 inhibitor) and HOTAIR-dependent "effector" -PRC2 (EZH2 inhibitors). The present approach will provide multiple-repression on HOTAIR generation, recruitment of PRC2 and nuclear histone modification and enzymatics activity of EZH2. Such strategy can provide novel basis for the combined treatment of multiple targets with the HOTAIR / PRC2 complex in gliomas, which will further support translational research of chemotherapy in glioma.