Harnessing the Oxidation Susceptibility of Deubiquitinases for Inhibition with Small Molecules

Abstract

Deubiquitinases (DUBs) counteract ubiquitination by removing or trimming ubiquitin chains to alter the signal. Their diverse role in biological processes and involvement in diseases have recently attracted great interest with regard to their mechanism and inhibition. It has been shown that some DUBs are regulated by reactive oxygen species (ROS) in which the catalytic Cys residue undergoes reversible oxidation, hence modulating DUBs activity under oxidative stress. Reported herein for the first time, the observation that small molecules, which are capable of generating ROS efficiently, inhibit DUBs by selective and nonreversible oxidation of the catalytic Cys residue. Interestingly, the small molecule beta‐lapachone, which is currently in clinical trials for cancer, is among the potent inhibitors, thus suggesting possible new cellular targets for its therapeutic effects. Our study describes a novel mechanism of DUBs inhibition and opens new opportunities in exploiting them for cancer therapy.

Advances in the Development Ubiquitin-Specific Peptidase (USP) Inhibitors

“…By screening a commercial library, a series of ortho quinones with considerable inhibition against USP2 at a concentration of 5 μM was identified [117]. Among them, Q29 (Figure 6) was at that time in advanced clinical trials for pancreatic cancer treatment.…”

An Oxidative Macrobicyclic Ring Opening of a Triptycene to a Highly Functionalized Fluorene Derivative

“…However, this has to be understood as a first hypothesis that has to be proven or disproven by further theoretical and experimental studies, which will be communicated in due course. It is worth mentioning that the nitroquinone motif has been found to be very attractive for pharmaceutical drug development. ,, In addition, quinones 1a–d will be used in condensation reactions with arene o -diamines to make new acceptors for organic electronics …”

Palladium‐Mediated Cleavage of Proteins with Thiazolidine‐Modified Backbone in Live Cells

“…Encouraged by our results with the model peptide, we designed a Ub analogue based on a Ubv2.3 construct that can be activated by Pd to generate Ubv2.3‐aldehyde to increase endogenous DUB inhibition in live cells. We chose to work with DU145 cells since they are known to express substantial levels of USP2a . We prepared the Ubv2.3 analogue 9 from three fragments, with addition of an Arg solubility tag fused to the N‐terminus of 9 via a flexible linker (Figure ; see Scheme S6).…”