随着后基因组时代对于表观遗传学研究的深入，对其调控机制的研究日益受到生物学家和药物研究者的重视。在更强调研发首创式药物的今天，我们迫切需要开展新靶点的确证研究。因此本申请选择表观遗传学领域中重要的组蛋白甲基化酶NSD2开展靶点确证和先导化合物发现研究。新药研发风险与机遇并存，因此靶点确证是从源头进行创新和规避风险的重要环节。我们将采用生物信息学方法对现有的NSD2相关的组学数据进行分析，提炼相互作用蛋白及信号通路信息，结合生物实验，确认信号通路的相关研究。在此基础上，开展靶点与疾病功能的研究，从而确证NSD2作为创新药物靶点的可行性。我们同步开展NSD2的活性化合物发现和优化研究。这将利用我们前期已建立的基于片段的药物发现平台，该平台已建立完善并有效开展了多项药物研发，取得了不俗的成绩。本申请拟采用该平台开展化合物发现工作，同时采用复合物晶体结构来指导化合物优化，为药物研发提供良好基础。

Epigenetics is a hot research field in post-genomics era, and its importance in gene regulation is gradually recognized by biologists, pharmacologists and medicinal chemists. Currently, we are urgently needing the first-in-class drug as they may provide better therapy for difficult deseases, such as cancer. Based on the importance of histone methyltransferases in cancer epigenetics, we selected NSD2 protein to study its biological funtions in cancer, with the aim to validate NSD2 as drug target. Then, in current application, we will analyze the deposited omics-data from NCBI GEO database, and collected information about interacted proteins and signaling pathways related to NSD2. We will perform the experiments to confirm the findings and validate the functions of NSD2. Meanwhile, we will adopt the fragment-based drug discovery(FBDD) method to identify novel active fragments, and conduct the ligand optimization. In current stage, we have built and successfully applied the FBDD platform to several projects with outstanding results. Also we have analyzed the omics-data, and set up the assay system for NSD2. We performed the fragment screening and obtained several active fragments and carried out lead optimization. In summary, we have solid bases to fulfill the proposed studies, and hope our study can validate the NSD2 as the cancer drug target, as well as provide new chemotypes for further drug development.