2. Academic Validation
  3. HDAC3 and HDAC8 PROTAC dual degrader reveals roles of histone acetylation in gene regulation

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

  • Cell Chem Biol. 2023 Nov 16;30(11):1421-1435.e12. doi: 10.1016/j.chembiol.2023.07.010.
Yufeng Xiao 1,  Seth Hale 2,  Nikee Awasthee 2,  Chengcheng Meng 2,  Xuan Zhang 1,  Yi Liu 1,  Haocheng Ding 3,  Zhiguang Huo 3,  Dongwen Lv 4,  Weizhou Zhang 5,  Mei He 6,  Guangrong Zheng 7,  Daiqing Liao 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
  • 2 Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
  • 3 Department of Biostatistics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
  • 4 Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
  • 5 Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA.
  • 6 Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA; UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA.
  • 7 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA; UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA. Electronic address: zhengg@cop.ufl.edu.
  • 8 Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA. Electronic address: dliao@ufl.edu.
PMID: 37572669 DOI: 10.1016/j.chembiol.2023.07.010
Abstract

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-selective 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 transcription. YX968 promotes Apoptosis and kills Cancer cells with a high potency in vitro. YX968 thus represents a new probe for dissecting the complex biological functions of HDAC3/8.

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