新型靶向抗肿瘤候选药物TOPK激酶抑制剂的筛选、设计和活性评价

According to the latest cancer statistics in China, the new incidences of cancer　were 4,292,000 and cancer deaths were 2,814,000 in 2015. The high incidence and　high mortality rate of tumors indicate that current approaches of prevention and　treatment cannot meet the needs. The demand for drugs with new mechanisms of　action, in particular, targeted and highly selective anti-tumor drugs is very　urgent. T-LAK cell-originated protein kinase (TOPK) was highly expressed in a wide varieties of tumor, including　breast cancer, colorectal cancer, lung cancer and leukemia etc. Its expression was　positively correlated with cancer malignant degree, and negatively correlated to　disease prognosis. TOPK is indispensable for the proliferation of tumor cells. It　not only regulates mitosis and cell cycle of tumor cells, but also involves in the　process of migration, invasion and apoptosis of tumor cells. It will be a　potentially important target for the cancer therapy. Based on the crystal structure of TOPK, the current project is to perform high throughput virtual ligand screening against the ZINC database,which has more than 20 million small organic molecules,　to select promising compounds for further activity assay. Then try to solve the　crystal structure of TOPK-inhibitor complex, based on the complex structure,　propose further modifications of the compounds. Finnally novel anti-cancer　lead compounds or drug candidates with our own interllectual

根据最新中国癌症统计数据，2015年我国癌症新发病例429.2万，死亡病例281.4万。肿瘤的高发病率和高致死率，表明目前预防和治疗手段远不能满足需要，对新作用机制、特别是靶向高选择性的抗肿瘤治疗药物需求很迫切。TOPK激酶在乳腺癌、结直肠癌、肺癌、白血病等多种肿瘤细胞中呈强表达，其表达量与癌症恶性程度正相关、和疾病预后负相关，它是肿瘤细胞增值所必需的，调控肿瘤细胞的有丝分裂和细胞周期，参与肿瘤细胞迁移、侵袭和凋亡的过程，是肿瘤治疗的潜在重要靶点。本项目通过基于TOPK晶体结构的虚拟筛选技术，对具有2千多万个有机小分子化合物的ZINC数据库进行高通量虚拟筛选，挑选有希望的化合物进行活性测定，然后解析抑制剂和TOPK复合物晶体结构，根据复合物晶体结构提出对化合物进行修饰和结构改造的方案，合成一系列化合物，进行药效学实验，从而得到拥有自主知识产权的新型靶向抗癌先导化合物或候选药物。

根据最新中国癌症统计数据，2015年我国癌症新发病例429.2万，死亡病例281.4万。肿瘤的高发病率和高致死率，表明目前预防和治疗手段远不能满足需要，对新作用机制、特别是靶向高选择性的抗肿瘤治疗药物需求很迫切。TOPK激酶在乳腺癌、结直肠癌、肺癌、白血病等多种肿瘤细胞中呈强表达，其表达量与癌症恶性程度正相关、和疾病预后负相关，它是肿瘤细胞增值所必需的，调控肿瘤细胞的有丝分裂和细胞周期，参与肿瘤细胞迁移、侵袭和凋亡的过程，是肿瘤治疗的潜在重要靶点。本项目通过蛋白质晶体学、计算生物学和药物化学的方法，寻找有效的TOPK抑制剂并对其进行活性评价,　最终发现泮托拉唑、艾普拉唑和HJ001等具有较强抗肿瘤活性的化合物，进行了体内外活性评价，特别对药效最好的HJ001进行了深入的研究，认为它是良好的先导化合物，值得进行进一步的临床前研究。在该项目的支持下，我们还在最新的蛋白靶向降解Protac技术上做了一些有益的探索，提出并实现了双重靶向降解技术（Dual Protacs）。