2. Academic Validation
  3. Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors

Identification and Structure-Activity Relationship of HDAC6 Zinc-Finger Ubiquitin Binding Domain Inhibitors

  • J Med Chem. 2018 May 24;61(10):4517-4527. doi: 10.1021/acs.jmedchem.8b00258.
Renato Ferreira de Freitas 1,  Rachel J Harding 1,  Ivan Franzoni 2,  Mani Ravichandran 1,  Mandeep K Mann 1,  Hui Ouyang 1,  Mark Lautens 2,  Vijayaratnam Santhakumar 1,  Cheryl H Arrowsmith 1 3,  Matthieu Schapira 1 4
Affiliations

Affiliations

  • 1 Structural Genomics Consortium , University of Toronto , MaRS South Tower, Suite 700, 101 College Street , Toronto , Ontario M5G 1L7 , Canada.
  • 2 Department of Chemistry, Davenport Chemical Laboratories , University of Toronto , 80 St. George Street , Toronto , Ontario M5S 3H6 Canada.
  • 3 Princess Margaret Cancer Centre , University Health Network , Toronto , Ontario , Canada.
  • 4 Department of Pharmacology and Toxicology , University of Toronto , Toronto , Ontario M5S 1A8 , Canada.
PMID: 29741882 DOI: 10.1021/acs.jmedchem.8b00258
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.

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