肿瘤是发病率和死亡率高的常见病。并发炎症可加重肿瘤对患者的危害。p97蛋白可调控泛素-蛋白酶体降解通路降解肿瘤和炎症相关蛋白。据此，申请人假设 p97抑制剂可同时抗肿瘤和抗炎，用前期研究检验了假设的科学性。即通过高通量筛选、抗肿瘤活性评价、抗炎活性评价及分子对接，确认了新先导结构PZL-6p是p97抑制剂，可同时抗肿瘤和抗炎。通过分子对接，申请人进一步确认PZL-6p结构修饰的PZZ-Ⅰ和PZZ-Ⅱ两系列共40种化合物的优越性。本项目拟合成这40种化合物、在细胞和动物水平评价抗肿瘤活性，在动物水平评价抗炎活性、检测对炎症因子和p97 ATP酶活性的抑制作用、模拟与p97活性位点的结合模式、分析构效关系、发现具有抗肿瘤和抗炎双重疗效的安全的p97抑制剂。实施本项目可阐明以抑制p97活性为关联机制，发现具有抗肿瘤和抗炎双重疗效的先导化合物，进而为临床治疗并发炎症的肿瘤患者提供候选药物。

Cancer is a leading cause of death with high morbidity and mortality. Inflammation has emerged as a major factor promoting cancer development.Finding a new target for chemotherapy drugs with dual antitumor and antiinflammation effect is a fundamental step in the path to curing cancer. The ubiquitin-proteasome system (UPS) degrade 80-90% of intracellular proteins. Cancer and inflammation cells exploit these protein degradation processes to increased their own growth and decrease apoptotic activity. The p97 AAA [ATPase associated with diverse cellular activities; also called VCP (valosin-containing protein)] participates in key steps in ubiquitin-dependent protein quality control, autophagy, membrane remodeling, and numerous other important cellular functions. p97 directs proteins to the UPS degradation systems. p97 is also an interesting target for cancer and inflammation therapeutics because it is known to be overproduced in multiple cancers, suggesting that its activity may be rate-limiting for the development of at least some types of cancer. Based on studies of p97 biology, we sought to identify small molecule inhibitors of p97. Our major hypothesis is that p97 inhibitors can control UPS processes, and that p97 is a molecular target for cancer therapy. Using high-throughput screening（HTS) and in vivo and in vitro antitumor and antiinflammation activitiy evaluation, we found 16 β-carboline derivatives PZL 6a-p. Our preliminary data show that among these 16 compounds, PZL-6p is a novel p97 inhibitor. Furthermore, normal human liver cell viabilities are unaffected by PZL- . In order to simplify structures for these lead compounds, we designed 40 compounds divided into two groups, PZZ-I and PZZ-II. We plan to synthesize and evaluate the activities of these compounds, including antitumor and antiinflammation activities in vivo and in vitro, inhibition of p97, interference mechanisms in the UPS pathways., acute toxicity and pharmacokinetics preliminary investigation and SAR analysis.Through this project, we will be able to establish a virtual screening model for p97 and its inhibitors and explore p97-linked anti-tumor and antiinflammation mechanisms of inhibiting the UPS system. The results are expected to help establish p97 inhibitors as potential agents for the treatment of tumors.