Abstract
Technologies that induce targeted protein degradation by small molecules have been developed recently. Chimeric small molecules such as Proteolysis Targeting Chimeras (PROTACs) and Specific and Non-genetic IAP-dependent Protein Erasers (SNIPERs), and E3 modulators such as thalidomides, hijack the cellular machinery for ubiquitylation, and the ubiquitylated proteins are subjected to proteasomal degradation. This has motivated drug development in industry and academia because “undruggable targets” can now be degraded by targeted protein degradation.
Highlights
Specialty section: This article was submitted to Chemical Biology, a section of the journal Frontiers in Chemistry
Technologies that induce targeted protein degradation by small molecules have been developed recently. Chimeric small molecules such as Proteolysis Targeting Chimeras (PROTACs) and Specific and Non-genetic inhibitor of apoptosis protein (IAP)-dependent Protein Erasers (SNIPERs), and E3 modulators such as thalidomides, hijack the cellular machinery for ubiquitylation, and the ubiquitylated proteins are subjected to proteasomal degradation
This class of molecules include fulvestrant, a selective estrogen receptor downregulator (SERD) against estrogen receptor-α (ERα) (Osborne et al, 2004) which is approved in the clinic against breast cancers expressing ERα, and a selective androgen receptor downregulator (SARD) against androgen receptor (AR) (Omlin et al, 2015) currently under clinical evaluation
Summary
Development of a therapeutic antibody and a small molecule inhibitor is the most successful strategy to develop novel molecular target drugs these days (Nelson et al, 2010; Ferguson and Gray, 2018). Many intracellular proteins without enzymatic activity are unable to be targeted by antibodies and small molecule inhibitors, and they are sometimes called “undruggable targets.”. These include scaffold proteins, transcription factors and splicing factors, and account for more than 70% of the proteins expressed in cells. Technologies to induce protein degradation by chimeric molecules, Proteolysis Targeting Chimeras (PROTACs) and Specific and Non-genetic IAP-dependent Protein Erasers (SNIPERs), have been developed, which enables rational design of degrader molecules against target proteins of interest. This mini-review provides an overview of the protein degradation technologies
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