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HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation

文献类型：期刊论文

作者Xiao, Yufeng10; Hale, Seth9; Awasthee, Nikee9; Meng, Chengcheng9; Zhang, Xuan3,10; Liu, Yi; Ding, Haocheng8; Huo, Zhiguang8; Lv, Dongwen1,2,7; Zhang, Weizhou6
刊名CELL CHEMICAL BIOLOGY
出版日期2023-11-16
卷号30期号:11页码:1421-+
ISSN号2451-9456
DOI10.1016/j.chembiol.2023.07.010
通讯作者Zheng, Guangrong(zhengg@cop.ufl.edu) ; Liao, Daiqing(dliao@ufl.edu)
英文摘要HDAC3 and HDAC8 have critical biological functions and represent highly sought-after therapeutic targets. Because histone deacetylases (HDACs) have a very conserved catalytic domain, developing isozyme-selec-tive inhibitors remains challenging. HDAC3/8 also have deacetylase-independent activity, which cannot be blocked by conventional enzymatic inhibitors. Proteolysis-targeting chimeras (PROTACs) can selectively degrade a target enzyme, abolishing both enzymatic and scaffolding function. Here, we report a novel HDAC3/8 dual degrader YX968 that induces highly potent, rapid, and selective degradation of both HDAC3/8 without triggering pan-HDAC inhibitory effects. Unbiased quantitative proteomic experiments confirmed its high selectivity. HDAC3/8 degradation by YX968 does not induce histone hyperacetylation and broad transcriptomic perturbation. Thus, histone hyperacetylation may be a major factor for altering tran-scription. YX968 promotes apoptosis and kills cancer cells with a high potency in vitro. YX968 thus repre-sents a new probe for dissecting the complex biological functions of HDAC3/8.
WOS关键词DEACETYLASE INHIBITORS ; SELECTIVE DEGRADATION ; EXPRESSION ANALYSIS ; IDENTIFICATION ; COMPLEX ; PROTEIN ; APOPTOSIS ; TRANSCRIPTION ; ENZYMES ; FAMILY
资助项目NIH[CA214608] ; NIH[CA218278] ; James and Esther King Biomedical Research Program, Florida Department of Health[22K05] ; UF Health Cancer Center ; DOD/CDMRP Breast Cancer Breakthrough Grant ; Dr. and Mrs. James Robert Spenser Family ; NIH/NCI[CA260239] ; NIH/NCI[CA269661]
WOS研究方向Biochemistry & Molecular Biology
语种英语
出版者CELL PRESS
WOS记录号WOS:001114231200001
源URL[http://119.78.100.183/handle/2S10ELR8/308077]  
专题中国科学院上海药物研究所
通讯作者Zheng, Guangrong; Liao, Daiqing
作者单位1.Univ Texas Hlth San Antonio, Ctr Innovat Drug Discovery, Sch Med, San Antonio, TX 78229 USA
2.Univ Texas Hlth San Antonio, Dept Biochem & Struct Biol, Sch Med, San Antonio, TX 78229 USA
3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
4.Univ Florida, UF Hlth Canc Ctr, Gainesville, FL 32610 USA
5.Univ Florida, Coll Pharm, Dept Pharmaceut, Gainesville, FL 32610 USA
6.Univ Florida, Coll Med, Dept Pathol Immunol & Lab Med, Gainesville, FL 32610 USA
7.Univ Florida, Coll Pharm, Dept Pharmacodynam, Gainesville, FL 32610 USA
8.Univ Florida, Coll Med, Dept Biostat, Gainesville, FL 32610 USA
9.Univ Florida, Coll Med, Dept Anat & Cell Biol, Gainesville, FL 32610 USA
10.Univ Florida, Coll Pharm, Dept Med Chem, Gainesville, FL 32610 USA
推荐引用方式
GB/T 7714		 Xiao, Yufeng,Hale, Seth,Awasthee, Nikee,et al. HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation[J]. CELL CHEMICAL BIOLOGY,2023,30(11):1421-+.
APA Xiao, Yufeng.,Hale, Seth.,Awasthee, Nikee.,Meng, Chengcheng.,Zhang, Xuan.,...&Liao, Daiqing.(2023).HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation.CELL CHEMICAL BIOLOGY,30(11),1421-+.
MLA Xiao, Yufeng,et al."HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation".CELL CHEMICAL BIOLOGY 30.11(2023):1421-+.

入库方式： OAI收割

来源：上海药物研究所

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