基于HDAC3蛋白降解探讨甘草次酸衍生物AH3抗三阴性乳腺癌的研究

三阴性乳腺癌（TNBC）转移潜能大、化疗预后差，是所有乳腺癌最棘手的一种，无有效的治疗靶点。HDAC3具有调控转录抑制和阻断凋亡作用，在TNBC中特异性高表达，与不良预后相关，是TNBC的潜在靶标。现有HDAC抑制剂为泛抑制剂，毒性大，HDAC3选择性抑制剂开发困难，靶向HDAC3蛋白降解是另一有效途径。我们发现甘草次酸衍生物AH3为一潜在的去泛素化酶和HDAC双靶点抑制剂，具有选择性降解HDAC3蛋白和抑制TNBC肿瘤细胞生长作用，是抑制HDAC3蛋白发挥抗TNBC的理想化合物。本申请拟解析HDAC3蛋白稳定体系和AH3诱导蛋白降解的分子机制；应用细胞和动物模型探讨HDAC3蛋白降解对TNBC生长、凋亡和侵袭的调节作用，为治疗TNBC提供新途径和新化合物。

Triple negative breast cancer (TNBC), with high metastasis and poor prognosis, is the most intractable in all breast cancer treatment without effective targets. HDAC3 plays an important role in regulating transcriptional inhibition and anti-apoptosis, HDAC3 is highly expressed in TNBC predicting poor prognosis and is a potential molecular target. It is difficult to develop selective HDAC3 inhibitors, and targeting HDAC3 to degradation is an alternative effective approach. We found that glycyrrhetinic acid derivative AH3, a potential deubiquitinating enzyme and HDAC dual target inhibitor, selectively degraded HDAC3 protein and inhibited TNBC cell growth. The present application will dissect the stabilization machinery of HDAC3 protein and identify the interrupting points of AH3 to cause HDAC3 degradation, as well as the antitumor effects of AH3 in cells and in xenograft models. We aim to provide a new approach to targeting TNBC through selectively inducing HDAC3 degradation.