靛玉红衍生的 PROTAC 靶向 HDAC6 减弱 NLRP3 炎性小体激活。
Attenuation of NLRP3 Inflammasome Activation by Indirubin-Derived PROTAC Targeting HDAC6.
机构信息
State Key Laboratory of Functions and Applications of Medicinal Plants, Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Provincial Key Laboratory of Pharmaceutics, School of Pharmacy, School of Basic Medicine, Guizhou Medical University, Guiyang 550004, China.
College of Life Sciences, University of Science and Technology of China, Hefei 230026, China.
出版信息
ACS Chem Biol. 2021 Dec 17;16(12):2746-2751. doi: 10.1021/acschembio.1c00681. Epub 2021 Dec 3.
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.
组蛋白去乙酰化酶 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 炎性小体的激活很重要，这表明靶向 HDAC6 可能有助于治疗许多炎症性疾病。本研究使用蛋白水解靶向嵌合体（PROTAC）策略，通过将源自天然产物靛玉红的选择性 HDAC6 抑制剂与 CRBN E3 配体泊马度胺连接，报告了一种具有低细胞毒性的 HDAC6 降解剂。我们的 HDAC6 降解剂能够有效地、选择性地降低几种细胞系（包括激活的 THP-1 细胞）中的 HDAC6 水平。该 HDAC6 降解剂的应用减弱了 LPS 诱导的小鼠中 NLRP3 炎性小体的激活，这首次证明了 HDAC6 PROTAC 可能是治疗 NLRP3 炎性小体相关疾病的一种新策略。
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