当前位置: X-MOL 学术ACS Chem. Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Attenuation of NLRP3 Inflammasome Activation by Indirubin-Derived PROTAC Targeting HDAC6
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-12-03 , DOI: 10.1021/acschembio.1c00681
Zhuoxian Cao 1 , Zhicheng Gu 1 , Shuxian Lin 1 , Di Chen 1 , Jie Wang 1 , Yonglong Zhao 1 , Yan Li 1 , Ting Liu 1 , Yongjun Li 1 , Yi Wang 2 , Hening Lin 3 , Bin He 1
Affiliation  

Histone deacetylase 6 (HDAC6) is a potential therapeutic target for treating several diseases. A recent study revealed that HDAC6 is important for NLRP3 inflammasome activation, suggesting that targeting HDAC6 could be useful for treating many inflammatory disorders. Using the proteolysis targeting chimera (PROTAC) strategy, we herein report an HDAC6 degrader with low cytotoxicity by tethering a selective HDAC6 inhibitor derived from a natural product, indirubin, with pomalidomide, a CRBN E3 ligand. Our HDAC6 degrader efficiently and selectively decreased HDAC6 levels in several cell lines, including activated THP-1 cells. Application of this HDAC6 degrader attenuated NLRP3 inflammasome activation in LPS-induced mice, which for the first time demonstrates that HDAC6 PROTAC could be a novel strategy to treat NLRP3 inflammasome-associated diseases.

中文翻译:


靛玉红衍生的 PROTAC 靶向 HDAC6 减弱 NLRP3 炎症小体激活



组蛋白脱乙酰酶 6 (HDAC6) 是治疗多种疾病的潜在治疗靶点。最近的一项研究表明,HDAC6 对于 NLRP3 炎症小体激活很重要,这表明靶向 HDAC6 可用于治疗许多炎症性疾病。使用蛋白水解靶向嵌合体 (PROTAC) 策略,我们在此报告了一种具有低细胞毒性的 HDAC6 降解剂,通过将源自天然产物靛玉红的选择性 HDAC6 抑制剂与 Pomalidomide(CRBN E3 配体)连接起来。我们的 HDAC6 降解剂可有效、选择性地降低多种细胞系(包括活化的 THP-1 细胞)中的 HDAC6 水平。这种 HDAC6 降解剂的应用减弱了 LPS 诱导的小鼠中 NLRP3 炎症小体的激活,这首次证明 HDAC6 PROTAC 可能是治疗 NLRP3 炎症小体相关疾病的新策略。
更新日期:2021-12-17
down
wechat
bug