Abstract
Ubiquitin–proteasome system (UPS) is a primary signaling pathway for regulation of intracellular protein levels. E3 ubiquitin ligases, substrate-specific members of the UPS, represent highly attractive protein targets for drug discovery. The importance of E3 ligases as prospective targets for small molecule modulation is reinforced by ever growing evidence of their role in cancer and other diseases. To date the number of potent compounds targeting E3 ligases remains rather low and their rational design constitutes a challenging task. To successfully address this problem one must take into consideration the multi-subunit nature of many E3 ligases that implies multiple druggable pockets and protein–protein interfaces. In this review, we briefly cover the current state of drug discovery in the field of RING-type E3 ligases with focus on MDM and Cullin families as targets. We also provide an overview of small molecule chimeras that induce RING-type E3-mediated proteasomal degradation of substrate proteins of interest.
Highlights
In the last two decades, scientists around the globe paid increasing attention toward Ubiquitin–proteasome system (UPS), a primary pathway for regulation of protein turnover and removal of misfolded proteins in eukaryotic cells
Examples of proteins selectively targeted by proteolysis-targeting chimera (PROTAC) via CRL2VHL-mediated mechanism include bromodomain and extra-terminal domain (BET) family of epigenetic regulators bromodomain-containing protein 2 (BRD2), BRD3, and
Many E3 ubiquitin ligases are implicated in cellular physiology and homeostasis at multiple regulatory levels, play crucial roles in a wide range of human diseases, including cancer and inflammatory disorders
Summary
In the last two decades, scientists around the globe paid increasing attention toward UPS, a primary pathway for regulation of protein turnover and removal of misfolded proteins in eukaryotic cells. Examples of proteins selectively targeted by PROTACs via CRL2VHL-mediated mechanism include BET family of epigenetic regulators BRD2, BRD3, and BRD4 (Zengerle et al, 2015; Raina et al, 2016; Gadd et al, 2017; Zhou et al, 2017; Chan et al, 2018), steroid hormone receptor ERRα and serine-threonine kinase RIPK2 (Bondeson et al, 2015) Another recent study demonstrated successful degradation of oncogenic tyrosine kinase BCR-ABL using both CRL2VHL- and CRL4ACRBN-specific PROTACs (Lai et al, 2016). SNIPERs, an abbreviated form of specific and non-genetic IAP-dependent protein erasers, are a class of small-molecule degraders similar to PROTACs (Itoh et al, 2010, 2011) These compounds recruit IAP family of RING-type E3 ligases – cIAP1, cIAP2, and XIAP. The initial concept was further explored by Naito laboratory that recently demonstrated selective proteasomal
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