Small molecules that target the ubiquitin system

Abstract

Eukaryotic life depends upon the interplay between vast networks of signaling pathways composed of upwards of 109–1010 proteins per cell. The integrity and normal operation of the cell requires that these proteins act in a precise spatial and temporal manner. The ubiquitin system is absolutely central to this process and perturbation of its function contributes directly to the onset and progression of a wide variety of diseases, including cancer, metabolic syndromes, neurodegenerative diseases, autoimmunity, inflammatory disorders, infectious diseases, and muscle dystrophies. Whilst the individual components and the overall architecture of the ubiquitin system have been delineated in some detail, how ubiquitination might be successfully targeted, or harnessed, to develop novel therapeutic approaches to the treatment of disease, currently remains relatively poorly understood. In this review, we will provide an overview of the current status of selected small molecule ubiquitin system inhibitors. We will further discuss the unique challenges of targeting this ubiquitous and highly complex machinery, and explore and highlight potential ways in which these challenges might be met.

Targeted modulation of E3 ligases using engineered ubiquitin variants

“…To date, there is only one type of FDA-approved drug targeting an E3 ligase and several candidate compounds that have advanced into clinical trials [45,54]. This class of FDA-approved drugs is the thalidomide compounds that target cereblon (CRBN), a protein that operates in the E3 ligase complex CRL4 [55,56].…”

Proteasome interaction with ubiquitinated substrates: from mechanisms to therapies

“…SOP11 and reduced thiolutin were found to also inhibit other JAMM metalloproteases, suggesting that additional optimization may be required for improved Rpn11 specificity. A more extensive review of these inhibitors can be found in [172,173].…”

Targeting E3 Ubiquitin Ligases and Deubiquitinases in Ciliopathy and Cancer

“…The screening of compounds for effects on protein ubiquitination and deubiquitination has led to the identification of a number of E3 ubiquitin ligase- and DUB-targeting drugs [ 29 , 165 , 177 ]. Because the substrates of these enzymes have a wide variety of functions, such drugs can interfere with various signaling pathways and impair physiological functions.…”

“…As noted, some of the E3 ubiquitin ligases and DUBs involved in the maintenance of ciliary protein stability may be therapeutic targets for the associated disorders. Indeed, small molecules targeting these E3 ubiquitin ligases and DUBs, including USP8, USP9X, CYLD, and VHL, have been successfully developed [ 29 , 177 , 186 ]. However, the role of E3 ubiquitin ligases and DUBs in disease can be context dependent [ 28 , 148 , 187 , 188 ].…”