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

View ORCID ProfileRenato Ferreira de Freitas, View ORCID ProfileRachel J. Harding, View ORCID ProfileIvan Franzoni, Mani Ravichandran, Mandeep K. Mann, Hui Ouyang, Mark Lautens, Vjayaratnam Santhakumar, View ORCID ProfileCheryl H. Arrowsmith, View ORCID ProfileMatthieu Schapira
doi: https://doi.org/10.1101/268557
Renato Ferreira de Freitas
1Structural Genomics Consortium, University of Toronto, MaRS South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7, Canada
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  • ORCID record for Renato Ferreira de Freitas
Rachel J. Harding
1Structural Genomics Consortium, University of Toronto, MaRS South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7, Canada
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Ivan Franzoni
2Department of Chemistry, Davenport Chemical Laboratories, 80 St. George St., University of Toronto, Toronto, Ontario, M5S 3H6 Canada
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Mani Ravichandran
1Structural Genomics Consortium, University of Toronto, MaRS South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7, Canada
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Mandeep K. Mann
1Structural Genomics Consortium, University of Toronto, MaRS South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7, Canada
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Hui Ouyang
1Structural Genomics Consortium, University of Toronto, MaRS South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7, Canada
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Mark Lautens
2Department of Chemistry, Davenport Chemical Laboratories, 80 St. George St., University of Toronto, Toronto, Ontario, M5S 3H6 Canada
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Vjayaratnam Santhakumar
1Structural Genomics Consortium, University of Toronto, MaRS South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7, Canada
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Cheryl H. Arrowsmith
1Structural Genomics Consortium, University of Toronto, MaRS South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7, Canada
3Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
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Matthieu Schapira
1Structural Genomics Consortium, University of Toronto, MaRS South Tower, Suite 700, 101 College Street, Toronto, ON M5G 1L7, Canada
4Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
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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 a 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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Posted February 20, 2018.
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Identification and Structure-Activity Relationship of HDAC6 Zinc-finger Ubiquitin Binding Domain Inhibitors
Renato Ferreira de Freitas, Rachel J. Harding, Ivan Franzoni, Mani Ravichandran, Mandeep K. Mann, Hui Ouyang, Mark Lautens, Vjayaratnam Santhakumar, Cheryl H. Arrowsmith, Matthieu Schapira
bioRxiv 268557; doi: https://doi.org/10.1101/268557
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Identification and Structure-Activity Relationship of HDAC6 Zinc-finger Ubiquitin Binding Domain Inhibitors
Renato Ferreira de Freitas, Rachel J. Harding, Ivan Franzoni, Mani Ravichandran, Mandeep K. Mann, Hui Ouyang, Mark Lautens, Vjayaratnam Santhakumar, Cheryl H. Arrowsmith, Matthieu Schapira
bioRxiv 268557; doi: https://doi.org/10.1101/268557

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