新型小分子化合物QW07靶向雄激素受体N端抑制去势抵抗性前列腺癌（CRPC）生长和转移的机理研究

前列腺癌发病率呈上升趋势，严重危害人类健康。雄激素剥夺治疗可以短期抑制前列腺癌，但大多数前列腺癌最终发展为去势抵抗性前列腺癌（CRPC），难以治愈。研究表明，雄激素受体N端 (AR-NTD)是研发抗CRPC药物的重要靶点。小分子化合物是新药研发的重要源泉，鉴定新的靶向小分子并研究其功能和机制有重要意义。申请者构建了靶向AR-NTD的筛选体系，鉴定到一种新的合成小分子化合物QW07选择性抑制AR阳性前列腺癌细胞增殖和克隆形成，并抑制动物模型CRPC的生长，且毒性较低；分子机制研究结果显示QW07可以和AR-NTD结合。但是尚不清楚QW07 对CRPC转移的影响及其确切分子机制。本项目围绕核心假设——QW07 通过靶向AR-NTD抑制CRPC生长和转移，研究QW07通过靶向AR-NTD抑制CRPC生长和转移的新功能和新机制。本课题对阐明小分子化合物抗肿瘤的分子机制及新药研发具有重要意义。

Prostate cancer (PCa) is the most common male cancer and seriously harms to human health because of its incidence and mortality rate showed an upward trend. Androgen deprivation therapy causes a temporary reduction in PCa tumor burden, but the tumor eventually develops into hard-to-cure castration-resistant prostate cancer (CRPC). Recent research showed that androgen receptor-N-terminal domain (AR-NTD) was the important drug target for CRPC. Small molecule compounds are important sources of new drug research and development. Therefore, it is very significant to identify new small molecules targeting AR-NTD and study the functions and mechanisms. Before application, we had set up a screening system and found a novel small molecule compound, QW07, which not only selectively inhibited AR positive prostate cancer cell growth and colony formation in vitro but also suppressed tumor growth in vivo with low side-effect. As for molecular mechanism，we found that QW07 bound to AR-NTD. However, the direct target, mechanism and the roles of QW07 in prostate cancer metastasis are still unknown. In this project, we provide the hypothesis that QW07 inhibits CRPC growth and metastasis by directly targeting the AR-NTD. We will further reveal the new functions and mechanisms of QW07 in prostate cancer growth and metastasis. This project is important for elucidating the anti-tumor mechanism of small molecule compounds and discovering new drugs.