Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 10, Pages 4517-4527Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00258
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Funding
- AbbVie [1097737]
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada through Ontario Genomics Institute [OGI-055]
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD] [115766]
- Janssen
- Merck KGaA, Darmstadt, Germany
- MSD
- Novartis Pharma AG
- Ontario Ministry of Research, Innovation and Science (MRIS)
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome [106169/ZZ14/Z]
- NSERC CREATE Grant [432008-2013]
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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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