RT Journal Article
SR Electronic
T1 Identification and Structure-Activity Relationship of HDAC6 Zinc-finger Ubiquitin Binding Domain Inhibitors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 268557
DO 10.1101/268557
A1 Renato Ferreira de Freitas
A1 Rachel J. Harding
A1 Ivan Franzoni
A1 Mani Ravichandran
A1 Mandeep K. Mann
A1 Hui Ouyang
A1 Mark Lautens
A1 Vjayaratnam Santhakumar
A1 Cheryl H. Arrowsmith
A1 Matthieu Schapira
YR 2018
UL http://biorxiv.org/content/early/2018/02/20/268557.abstract
AB 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.