靶向自噬关键分子Atg4B的新型小分子化合物设计合成及其抗乳腺癌机制研究

Autophagy is a research hotspot at home and abroad in recent years. The mechanism study of anti-tumor drugs centered on autophagy has become a new strategy for cancer therapy. Using systems biology network, we found that Atg4B is a new potential target for breast cancer therapy, as a critical regulator in autophagy regulation network. In our previous work, we discovered a small molecule compound Flubendazole by virtual screening, which induces autophagic death by activating Atg4B both in vitro and in vivo in breast cancer. Moreover, we synthesized a series compounds and screened a selective lead compound F-202. In this project, based on the structure-activity relationship, we proposed to further optimize the structure of F-202 to improve its targeted selectivity and specificity, obtaining an optimal compound can improve its anti-tumor activity and autophagy-modulating activity in breast cancer. We will also demonstrate the autophagy-regulation mechanism of the optimal compound in vivo and in vitro, and identify the molecular mechanisms of its targeted Atg4B. These findings will help designing a novel synthesized small-molecule Atg4B agonist, which would be utilized as a specific, targeted anti-tumor compound with autophagy-modulating mechanisms in breast cancer therapy, thus providing new ideas for development of novel targeted small molecule compound in breast cancer.

自噬是近年来国内外研究的热点，围绕自噬及其信号进行抗肿瘤药物机制研究成为一种新颖策略。利用系统生物学网络，我们发现处于自噬调控网络的关键调控子Atg4B，是乳腺癌治疗潜在的新靶点。在前期工作中，我们通过虚拟筛选发现Flubendazole在乳腺癌体内外模型中通过激活Atg4B调控自噬性死亡，并进一步基于结构改造和系列筛选获得了具有选择性的先导化合物F-202。在本项目中，基于前期的构效关系研究，我们拟将F-202的结构进一步优化设计，提高其靶向性和专一性，以期得到的优选化合物能提高其对乳腺癌的抗肿瘤活性和增强其诱导自噬性死亡的效果。我们还将重点阐明优选化合物在体内外诱导的自噬机制，并明确其靶向Atg4B的分子机制。本研究将有助于确认设计合成新型小分子Atg4B激动剂作为抗肿瘤特异性靶向化合物调控自噬的分子机制,为开发新型靶向乳腺癌小分子药物提供新思路。

自噬是近年来国内外研究的热点，围绕自噬及其信号进行抗肿瘤药物机制研究成为一种新颖策略。利用系统生物学网络，我们发现处于自噬调控网络的关键调控子Atg4B，是乳腺癌治疗潜在的新靶点。在前期工作中，我们基于结构改造和系列筛选获得了一些具有选择性的先导化合物。随后，我们在先导化合物的基础上，合成了44个候选化合物，并通过活性筛选，获得了一个结构新颖，具有较高活性，毒副作用较低的抗乳腺癌候选药物33。在细胞分子水平的机制研究发现化合物33可以靶向靶向Atg4B诱导肿瘤细胞发生自噬性细胞死亡和凋亡，动物水平研究发现在小鼠异种移植瘤模型中化合物33表现出显著的抗乳腺癌疗效且无明显毒副作用。在本项目的资助下，项目负责人在Chem Sci, JMC，APSB，BMCL等期刊共发表论文10篇，其中第一作者或通讯作者发表论文9篇。