Small‐Molecule PROTACS: New Approaches to Protein Degradation

Abstract

The current inhibitor-based approach to therapeutics has inherent limitations owing to its occupancy-based model: 1) there is a need to maintain high systemic exposure to ensure sufficient in vivo inhibition, 2) high in vivo concentrations bring potential for off-target side effects, and 3) there is a need to bind to an active site, thus limiting the drug target space. As an alternative, induced protein degradation lacks these limitations. Based on an event-driven model, this approach offers a novel catalytic mechanism to irreversibly inhibit protein function by targeting protein destruction through recruitment to the cellular quality control machinery. Prior protein degrading strategies have lacked therapeutic potential. However, recent reports of small-molecule-based proteolysis-targeting chimeras (PROTACs) have demonstrated that this technology can effectively decrease the cellular levels of several protein classes.

Degrons in cancer

“…The degron was recognized by b-TrCP, which targeted METAP2 for proteasomal degradation. PROTAC technology has already been successfully applied to various E3 ligases in preclinical experiments (347,348).…”

Drug discovery beyond the rule of 5 - Opportunities and challenges

“…This may be of particular concern for intracellular targets with large, flat, or groove-shaped binding sites that are unable to be modulated with Ro5 compliant compounds, but can be drugged by orally available and cell permeable compounds in bRo5 space, such as macrocycles [3,5,6]. Very flexible or unstructured targets are still far from being drugged in a rational way by small molecules and may require completely novel approaches such as interference at the expression/RNA level or tagging the target protein for degradation [16].…”

Concepts to Target MYC in Pancreatic Cancer

“…84). PROTACs are bifunctional inhibitors that bind to the target of interest and in addition with a second moiety to E3 ligases (85). Thus, PROTACs hijack the intracellular protein ubiquitination machinery to degrade the target of interest (85).…”

“…PROTACs are bifunctional inhibitors that bind to the target of interest and in addition with a second moiety to E3 ligases (85). Thus, PROTACs hijack the intracellular protein ubiquitination machinery to degrade the target of interest (85). The phthalimideconjugated BET-inhibitor dBET1 recruits cereblon, a protein of the cullin-RING ubiquitin ligase (CRL) complex, to ubiquitinate and degrade BRD4 and the BET family members BRD2 and BRD3 (84).…”