组蛋白甲基转移酶NSD3抑制剂的发现及其抗肺癌活性研究

Lung cancer is the most frequent cause of cancer-related deaths both in China and worldwide. Identification of novel targets and small molecular drugs against lung cancer would reduce morbidity and mortality in patients and improve the quality of life and symptoms of patients with lung cancer. Histone methyltransferase NSD3 have crucial roles in lung carcinogenesis, and have been recognized as a promising target for lung cancer therapy. In this application, we plan to identify a set of NSD3 inhibitors via virtual screening combined with bioassays. Here, compounds from ChemDiv library will be screened based on high throughput virtual screening, and the inhibitory activities will be examined in vitro followed by further conformation in NSCLC cells. Finally, the anti-tumor activity and relative mechanism of candidate inhibitors will be evaluated in NSCLC cells and corresponding xenograft models. These studies will facilitate further optimization and application for the development of novel NSD3 inhibitors.

肺癌是目前中国及全世界范围内发病率与死亡率最高的恶性肿瘤，发现新的抗肺癌治疗靶点及抗癌药物对降低死亡率、提高病人生存质量具有十分重要的意义。组蛋白甲基转移酶NSD3在肺癌的发生发展中发挥重要作用，是一个潜在的抗肿瘤靶标。本项目将采用计算机虚拟筛选结合实验的基本策略，致力于发现高活性的NSD3抑制剂。主要包括：构建计算机虚拟筛选评估模型，并针对ChemDiv库化合物进行筛选发现NSD3候选抑制剂；测定化合物在体外、细胞内的酶活性；结合细胞、动物实验系统评价化合物抗肺癌活性及作用机制。这些研究为新型NSD3抑制剂先导化合物的开发提供了实验依据，为基于NSD3的靶向抗肺癌药物的发现奠定了理论基础。