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
  • 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: [email protected].
  • 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: [email protected].
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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