期刊
ACS CHEMICAL BIOLOGY
卷 16, 期 12, 页码 2746-2751出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.1c00681
关键词
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资金
- National Natural Science Foundation of China [82160655, U1812403-05, 81960628, 21662010]
- Guizhou Science and Technology Department of China [[2019]2760, [2020]1Y395, [2020]4Y206, [2018] 5779-68]
- Guiyang Municipal Science and Technology Project [[2017]30-18, [2017]30-38]
HDAC6 is a potential therapeutic target for treating various diseases, and a degrader targeting HDAC6 can efficiently reduce its levels in cells and attenuate NLRP3 inflammasome activation.
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.
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