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R E V I E W S
Although the genomic revolution has allowed a plethora of novel protein targets to be linked to disease states14,
standard small-molecule drug discovery strategies are unable to exploit all of these opportunities, because many of these potential targets do not have suitable binding pockets that directly modulate protein function5. Owing to their intracellular location, such proteins are often not tractable targets for antibody therapeutics either. The challenge that this presents for drug discovery is highlighted by the fact that there are very few marketed drugs that target scaffolding proteins, transcription factors and other non-enzymatic proteins inside the cell6,7.
Furthermore, small-molecule therapeutic strategies that focus on occupation of a binding site on a protein may require high systemic drug exposures to achieve sufficient site occupancy invivo8 and thus potentially increase the risk of off-target adverse effects.
One method for modulating intracellular protein concentrations is through nucleic acid-based agents such as antisense oligonucleotides (ASOs) or agents that exploit RNA interference (RNAi), such as small interfering RNAs (siRNAs). More recently, the advent of CRISPRCas9 technology9,10 offers the potential of modifying the genome itself to achieve gene knockout; however, the clinical potential of this technology is yet to be explored (see recent reviews1113). Although nucleic acid-based tools have proved to be useful in research, the development of these agents as drug candidates has faced many challenges: unmodified nucleotides are
highly unstable in serum14, whereas modified nucleotides tend to accumulate in the kidney15,16 and can be immunogenic17,18. Nucleic acid-based agents encapsulated by nano particles to improve their delivery properties are still captured in the liver1922. In addition, RNAi can engage off-target mRNA, which leads to undesired effects2325.
Finally, efficacy is ultimately dependent on the target protein half-life; thus, long-lived proteins are less affected by these approaches. For a more detailed analysis, the reader is referred to these excellent reviews2628. Although significant progress has been made, as indicated by the many ongoing clinical trials, only two ASO therapeutics (fomirisen29 and mipomersen30) that reduce the production of a particular protein have been approved in the United States31.
Small-molecule-induced protein degradation is emerging as a strategy that also has the potential to target a broader range of proteins than standard small-molecule strategies that focus on binding...