Re-evaluating the mechanism of action of DUB inhibitors

DUB inhibitors found to induce non-specific protein aggregation

Congratulations to former group member Dr Jenny Ward on her latest publication to the Journal of Medicinal Chemistry, featuring research conducted in the Tate group.

The collaborative research with the Structural Genomics Consortium, University of Oxford, aimed to study the mechanism of action (MOA) of deubiquitinating enzymes (DUBs). DUBs are an important class of enzymes which have been reported to target multiple disease states, with several known DUBs inhibitors reported in literature. However, little is known about their MOA so two structurally-related α,β-unsaturated carbonyl-containing DUB inhibitors (b-AP15 and VLX1570) were studied for their unspecific protein cross-linking within Michael Acceptor-containing drugs.

The experiments demonstrated that these compounds target a diverse range of proteins, resulting in the formation of higher molecular weight (MW) complexes. The work also identified CIAPIN1 as a sub-micromolar covalent target of VLX1570, following activity-based proteome profiling, Further analysis demonstrated that high MW complex formation leads to aggregation of CIAPIN1 in intact cells and the results suggest that in addition to DUB inhibition, these compounds induce nonspecific protein aggregation, providing molecular explanation for general cellular toxicity.

Well done and thank you to all those involved in this research!

Dr Ward’s research in the Tate group was supported by the EPSRC.