Abstract
New therapeutic modalities are needed to address the problem of pathological but undruggable proteins. One possible approach is the induction of protein degradation by chimeric drugs composed of a ubiquitin ligase (E3) ligand coupled to a ligand for the target protein. This article reviews chimeric drugs that decrease the level of specific proteins such as proteolysis targeting chimeric molecules (PROTACs) and specific and nongenetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs), which target proteins for proteasome-mediated degradation. We cover strategies for increasing the degradation activity induced by small molecules, and their scope for application to undruggable proteins.
Highlights
Conventional small-molecular drug discovery has relied on the lock-and-key theory, that is, discovery/optimization of small-molecular drugs that bind to target proteins and modulate their functions
That is, the induction of protein degradation by chimeric drugs composed of an E3 ligand and a target protein ligand, represents a highly promising new modality for drug discovery
Both selective knockdown of the target protein, and double knockdown of the target protein/cellular inhibitor of apoptosis protein 1 (cIAP1) were achieved by changing the chemical structure of the cIAP1 ligand
Summary
Conventional small-molecular drug discovery has relied on the lock-and-key theory, that is, discovery/optimization of small-molecular drugs that bind to target proteins and modulate their functions. It is difficult to modulate the functions of other proteins, such as substrate-binding proteins, aggregation-prone proteins, protein–protein complexes, and so on, because few drug-like modulators of such proteins have been identified so far. An estimated 60% of small-molecular drug discovery projects fail during hit-to-lead development because the biological target protein is found to be “undruggable”, that is, the protein cannot bind to compounds with appropriate drug-like properties [1]. In addition to potential pharmaceutical applications, techniques for decreasing the expression levels of proteins are useful for analysis of the functions of proteins of interest. This review article covers chimeric drugs that decrease the levels of target proteins via inhibitor of apoptosis proteins (IAP)-mediated ubiquitination, focusing in particular upon our work on protein degraders termed specific and non-genetic inhibitor of apoptosis protein (IAP)-dependent protein erasers (SNIPERs) in addition to important proteolysis targeting chimeric molecules (PROTACs)
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