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

Ferreira de Freitas, R.; Harding, R.; Franzoni, I.; Ravichandran, M.; Mann, M. K.; Ouyang, H.; Lautens, M.; Santhakumar, V.; Arrowsmith, C.; Schapira, M.

doi:10.1101/268557

bioRxiv · 10.1101/268557

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

Ferreira de Freitas, R.·Harding, R.·Franzoni, I.·Ravichandran, M.·Mann, M. K.·Ouyang, H.·Lautens, M.·Santhakumar, V.·Arrowsmith, C.·Schapira, M.

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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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Ferreira de Freitas, R., Harding, R., Franzoni, I., Ravichandran, M., Mann, M. K., Ouyang, H., Lautens, M., Santhakumar, V., Arrowsmith, C., Schapira, M.. 2018-02-20. Identification and Structure-Activity Relationship of HDAC6 Zinc-finger Ubiquitin Binding Domain Inhibitors. https://doi.org/10.1101/268557

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