2. Academic Validation
  3. Discovery of a Highly Potent and Selective HDAC8 Degrader: Advancing the Functional Understanding and Therapeutic Potential of HDAC8

Discovery of a Highly Potent and Selective HDAC8 Degrader: Advancing the Functional Understanding and Therapeutic Potential of HDAC8

  • J Med Chem. 2024 Jul 1. doi: 10.1021/acs.jmedchem.4c00761.
Yufeng Xiao 1,  Nikee Awasthee 2,  Yi Liu 1,  Chengcheng Meng 2,  Michael Y He 3,  Seth Hale 2,  Rashmi Karki 4,  Zongtao Lin 4,  Megan Mosterio 5,  Benjamin A Garcia 4,  Robert Kridel 3,  Daiqing Liao 2,  Guangrong Zheng 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
  • 2 Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, Florida 32610, United States.
  • 3 Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
  • 4 Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63110, United States.
  • 5 Department of Chemistry, University of Florida, Gainesville, Florida 32610, United States.
PMID: 38949959 DOI: 10.1021/acs.jmedchem.4c00761
Abstract

HDAC8 plays crucial roles in biological processes, from gene regulation to cell motility, making it a highly desirable target for therapeutic intervention. HDAC8 also has deacetylase-independent activity which cannot be blocked by a conventional inhibitor. In this study, we report the discovery of YX862, a highly potent and selective hydrazide-based HDAC8-proteolysis targeting chimera (PROTAC) degrader. The selectivity is achieved through rational design of the warhead to spare HDAC3 activity from the previous HDAC3/8 dual degrader YX968. We demonstrate that the degradation of HDAC8 by YX862 increases acetylation levels of its nonhistone substrates such as SMC3 without significantly triggering histone PTM, supporting HDAC8's major role in nonhistone PTM regulation. YX862 exhibits promising on-target antiproliferative activity against DLBCL cells with higher potency than the HDAC8 selective inhibitor PCI-34051. As a selective HDAC8 Degrader that avoids pan-HDAC inhibition, YX862 represents a valuable tool for exploring the biological and therapeutic potential of HDAC8.

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