Chemically Induced Cellular Proteolysis: An Emerging Therapeutic Strategy for Undruggable Targets
Seonghyeon Moon1, and Byung-Hoon Lee1,*
1Department of New Biology, DGIST, Daegu 42988, Korea
Received September 4, 2018; Revised October 28, 2018; Accepted October 30, 2018.; Published online November 7, 2018.
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Traditionally, small-molecule or antibody-based therapies against human diseases have been designed to inhibit the enzymatic activity or compete for the ligand binding sites of pathological target proteins. Despite its demonstrated effectiveness, such as in cancer treatment, this approach is often limited by recurring drug resistance. More importantly, not all molecular targets are enzymes or receptors with druggable ‘hot spots’ that can be directly occupied by active site-directed inhibitors. Recently, a promising new paradigm has been created, in which small-molecule chemicals harness the naturally occurring protein quality control machinery of the ubiquitin-proteasome system to specifically eradicate diseasecausing proteins in cells. Such ‘chemically induced protein degradation’ may provide unprecedented opportunities for targeting proteins that are inherently undruggable, such as structural scaffolds and other non-enzymatic molecules, for therapeutic purposes. This review focuses on surveying recent progress in developing E3-guided proteolysis-targeting chimeras (PROTACs) and small-molecule chemical modulators of deubiquitinating enzymes upstream of or on the proteasome.
Keywords: deubiquitinating enzyme, induced proteolysis, PROTAC, small-molecules, ubiquitin-proteasome system, undruggable target

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31 October 2018 Volume 41,
Number 10, pp. 881~932

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