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Updated: Feb 10, 2026
Direct Protein Delivery to Mammalian Cells Using Cell-permeable Cys2-His2 Zinc-finger Domains
Published on: March 25, 2015
Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors
Renato Ferreira de Freitas1, Rachel J Harding1, Ivan Franzoni2
1Structural Genomics Consortium , University of Toronto , MaRS South Tower, Suite 700, 101 College Street , Toronto , Ontario M5G 1L7 , Canada.
Abstract:
HDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of an HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155, are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.
Insights
Researchers discovered new inhibitors targeting the HDAC6 zinc-finger ubiquitin-binding domain (ZnF-UBD), offering a novel approach for multiple myeloma treatment. These compounds disrupt protein aggregate clearance, complementing proteasome inhibitor therapies.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Histone deacetylase 6 (HDAC6) is crucial for clearing protein aggregates via lysosomes.
- HDAC6 is a potential therapeutic target in multiple myeloma, especially in combination with proteasome inhibitors.
- Targeting the HDAC6 zinc-finger ubiquitin-binding domain (ZnF-UBD) offers an alternative to direct catalytic inhibition.
Purpose of the Study:
- To discover and develop novel small molecules that inhibit HDAC6 by targeting its ZnF-UBD.
- To explore the structure-activity relationships of these inhibitors.
- To assess the potential of ZnF-UBD inhibitors for multiple myeloma treatment.
Main Methods:
- Virtual screening to identify initial hits.
- Chemical synthesis and optimization of lead compounds.
- Biochemical assays to determine inhibitory activity (low micromolar range).
- Crystallography to elucidate binding modes and guide further development (nine crystal structures obtained).
Main Results:
- Discovery of a novel chemical series targeting the HDAC6 ZnF-UBD.
- Identification of key structural features for activity: a ubiquitin C-terminal mimicry and an extended aromatic system.
- One compound induced a conformational change, opening a secondary binding pocket.
- Preliminary structure-activity relationships were established.
Conclusions:
- The developed compounds are potent inhibitors of the HDAC6 ZnF-UBD.
- Targeting the ZnF-UBD is a viable strategy for developing new therapeutics.
- Further optimization could lead to a chemical probe for investigating HDAC6's role in multiple myeloma and other diseases.
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