淋巴瘤精确治疗的挑战主要源自分子遗传的高度异质性，发现新的治疗靶点和小分子药物有利于优化治疗策略。DL01是我们通过表型筛选获得的小分子化合物，能在体内外显著杀伤淋巴瘤细胞。前期工作证实，除了诱导DNA损伤之外，DL01明显抑制c-Myc和BCL6等重要生存基因的转录从而促进细胞凋亡，提示DL01具有多重抗淋巴瘤机制，但其作用靶点仍然未知。本项目运用药物亲和反应靶标稳定性（DARTS）技术联合HuProt蛋白质组芯片寻找和鉴定DL01靶点；采用亲和纯化，siRNA，免疫印迹，基因表达谱分析以及染色质免疫共沉淀等方法，初步阐明DL01的分子作用机制，尤其是靶点可能对转录的表观遗传调控；结合动物实验和临床资料分析，明确DL01靶点的生物学意义。通过这一系列研究，不仅为淋巴瘤提供新的治疗靶点，而且为DL01作为抗淋巴瘤新药的进一步研发提供依据。

The major challenge for precision therapy of diffuse large B cell lymphoma (DLBCL) lies in its tremendous underlying molecular hetergeneity, and discovery of therapeutic targets and small molecule agents is essential for treatment optimization. DL01, a novel small molecule compound indentified through phenotypic screening, significantly kills lymphoma cells in vitro and in vivo. DL01 induces DNA damage, interestingly, it also represses transcriptions of several critical pro-survival genes such as c-Myc and BCL6, suggesting its multiple mechanisms of action. However, the cellular targets of DL01 remains unknown. In this proposal, integration of DARTS (Drug Affinity Responsive Target Stability）techinique and HuProt proteome microarray will be applied to identify the DL01 targets. With affinity purification, RNA interference, immunoblot, chromatin immunoprecipitation, we aim to elucidate the mechanisms by which DL01 induces apoptosis of lymphoma cells, especially the potential role of DL01 targets in epigenetc transcriptional regulation. Furthermore,we try to determine the physiologic relevance of the targets by animal model and clinic studies. Thus, we would reveal novel therapeutic targets for DLBCL, and provide evidence supporting further development of DL01 as a novel anti-lymphoma agent.