Structure-Guided Design of a Small-Molecule Activator of Sirtuin-3 that Modulates Autophagy in Triple Negative Breast Cancer
Structure-Guided Design of a Small-Molecule Activator of Sirtuin-3 that Modulates Autophagy in Triple Negative Breast Cancer
复制标题
结构引导设计一种调节三阴性乳腺癌自噬的 Sirtuin-3 小分子激活剂
DOI：
10.1021/acs.jmedchem.0c02268
复制
发表时间：
2021
影响因子：
7.3
通讯作者：
Liu Bo
中科院分区：
文献类型：
--
作者：
Zhang Jin;Zou Ling;Shi Danfeng;Liu Jie;Zhang Jifa;Zhao Rongyan;Wang Guan;Zhang Lan;Ouyang Liang;Liu Bo
Sirtuin-3 (SIRT3) is an NAD+-dependent protein deacetylase localized primarily in the mitochondria with many links to different types of human cancers. Autophagy, which is a highly conserved lysosomal degradation process in eukaryotic cells, has been recently reported to be positively regulated by SIRT3 in cancer; therefore, activating SIRT3-modulated autophagy may be a promising strategy for drug discovery. In this study, we discovered a small-molecule activator of SIRT3 compound33c(ADTL-SA1215) with specific SIRT3 deacetylase activity by structure-guided design and high-throughput screening. Subsequently, compound33cinhibited the proliferation and migration of human breast carcinoma MDA-MB-231 cells by SIRT3-driven autophagy/mitophagy signaling pathwaysin vitroandin vivo.Collectively, these results demonstrate that pharmacological activation of SIRT3 is a potential therapeutic approach of triple negative breast cancer (TNBC). More importantly, compound33cmay be a first-in-class specific small-molecule activator of SIRT3 that would be utilized for future cancer drug development.
