新型小分子化合物ZY-444靶向丙酮酸羧化酶抑制乳腺癌生长和转移的机理研究

Breast cancer is a common female cancer and seriously harms to human health. And its incidence and mortality rate showed an upward trend. The growth, metastasis and recurrence of breast cancer are the main causes of death in breast cancer patients. Recent researches have shown that the progression of breast cancer requires excessive metabolism, and pyruvate carboxylase (PC) is an important drug target of breast cancer. Small molecule compounds are important sources of new drug research and development. Identifying new small molecule targeted drugs provide new effective strategies for breast cancer treatment, and studying their functions and mechanisms is of great significance. The applicant has established at argeted screening system for breast cancer metabolism and identified a novel small molecule ZY-444. ZY-444 inhibit breast cancer growth，metastasis and recurrencewith low toxicity. Molecular mechanism results showed that ZY-444 bind PC and inhibit its enzyme activity, affect the metabolism related signaling pathways and inhibit the proliferation and migration of breast cancer cells. However, the exact binding sites and specific molecular mechanisms of ZY-444 and PC are not clear. This project focuses on the core hypothesis that ZY-444 inhibits breast cancer growth, metastasis and recurrence by directly targeting PC.We will further reveal the new functions and mechanisms of ZY-444 in breast cancer. This project is important for elucidating the anti-tumor mechanism of small molecule compounds and discovering new drugs.

乳腺癌是女性常见恶性肿瘤，其发病率呈上升趋势，严重危害人类健康。乳腺癌的生长、转移和复发是患者死亡的主要原因。乳腺癌的进展需要异常代谢维持，丙酮酸羧化酶（pyruvate carboxylase，PC）是乳腺癌的重要药物靶点。小分子化合物是新药研发的重要源泉，鉴定新型小分子靶向药物可以为乳腺癌治疗提供新的有效策略，研究其功能和机制具有重要意义。申请者通过构建靶向乳腺癌代谢的筛选体系，鉴定到了一种新型小分子化合物ZY-444可以抑制乳腺癌生长、转移和复发，且毒性较低。分子机理上，ZY-444结合PC并抑制其酶活，影响代谢相关信号途径、进而抑制乳腺癌细胞增殖和迁移。但是，ZY-444与PC确切的结合位点和具体分子机制尚不清楚。本项目围绕核心假设—ZY-444靶向PC抑制乳腺癌生长、转移和复发，研究其新功能和新机制。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。

乳腺癌是女性常见恶性肿瘤，其发病率呈上升趋势，严重危害人类健康。乳腺癌的生长、转移和复发是患者死亡的主要原因。小分子化合物是新药研发的重要源泉，目前市场在售的药物大多数属于小分子化合物。鉴定新的抗乳腺癌小分子化合物、发现其靶点并揭示其分子机制，不仅可以为新药研发提供新思路，也可为后期新药研发奠定基础，具有理论和实践的双重意义。.乳腺癌的进展需要异常代谢维持，丙酮酸羧化酶（pyruvate carboxylase，PC）作为异常代谢的关键酶，是乳腺癌的重要药物靶点。申请者通过构建靶向乳腺癌代谢的筛选体系，鉴定到了一种新型小分子化合物ZY-444可以抑制乳腺癌生长、转移和复发，且毒性较低。分子机理上，ZY-444结合PC，不影响其表达但可抑制PC酶活性，微阵列分析结果证实ZY-444主要调节癌症代谢相关的基因，抑制Wnt/β-Catenin/Snial信号通路，进而抑制乳腺癌细胞增殖和迁移。同时，敲低PC可明显降低ZY-444的抗增殖能力，显示ZY-444的药效需要PC的存在。细胞水平上，ZY-444抑制了多株PC高表达细胞的增殖，包括MDA-MB231、4T1、HT29、MKN45、Huh-7等细胞，而对PC表达正常的细胞药效较差。动物水平上，ZY-444抑制人源三阴性乳腺肿瘤原位生长和转移，抑制乳腺癌和延长小鼠生存期，抑制乳腺癌切除术后的局部复发和远端转移。