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PROTAC
PROTACs (a.k.a. protein degraders) are heterobifunctional small molecules which are made up of three portions: 1) An E3 ligand component, which recruits the E3 ligase to associate with the target protein. 2) A chemical linker, which conjugates the E3 ligand component to the ligand bound to the target protein. It has been shown that the linker design is crucial for the potency, permeability, and stability. Finally, 3) A target protein ligand, which binds the target protein(Fig. 1) [3]. Hence, PROTACs can recruit the E3 ligase and enable the transfer of ubiquitin to the target protein. The polyubiquitin-tagged target protein is subsequently recognized and degraded by the proteasome (Fig. 1) [3]. In recent years, numerous E3 ligases (e.g., MDM2, cIAP1, cereblon and von Hippel-Lindau (VHL)) have been shown to be recruited by PROTAC-tagged target proteins and have been validated to enable the degradation of the target protein. In addition, functionally and structurally diverse target proteins can be efficiently degraded with the utilization of PROTACs. Transcription factors such as AR, ER and ERRα are successfully degraded by employing small molecule PROTACs.
An exciting example of the application of PROTAC technology for protein degradation has been shown by targeting BRD4.PROTACs can selectively induce the target protein degradation among structurally similar targets.PROTACs may induce tumor regression at lower dosages since PROTACs regulate the functional target protein abundance by chemical knock down rather than by inhibition. Second, selectivity for both E3 ligases and the target protein contributes to another advantage of PROTACs. Different E3 ligases possess differential degradation profiles, which can lead to high selectivity and specificity for controlling protein knock down [16]. In addition, the surface contacts of the E3, E2, and ubiquitin complex that is recruited to the target protein also contributes to selectivity. Third, PROTACs are novel drug candidates that have shown the potential to overcome instances of binding site mutation-induced drug resistance. In theory, the PROTACs function is not mediated by binding to an active site for inhibition. Thus, PROTACs may be designed to engage with target proteins at residues that do not undergo the same degree of evolutionary pressure to mutate, compared to residues within an active site or catalytic domain.
References
1.Wang P, Zhou J. Curr Top Med Chem. 2018;18(16):1354–1356.
An exciting example of the application of PROTAC technology for protein degradation has been shown by targeting BRD4.PROTACs can selectively induce the target protein degradation among structurally similar targets.PROTACs may induce tumor regression at lower dosages since PROTACs regulate the functional target protein abundance by chemical knock down rather than by inhibition. Second, selectivity for both E3 ligases and the target protein contributes to another advantage of PROTACs. Different E3 ligases possess differential degradation profiles, which can lead to high selectivity and specificity for controlling protein knock down [16]. In addition, the surface contacts of the E3, E2, and ubiquitin complex that is recruited to the target protein also contributes to selectivity. Third, PROTACs are novel drug candidates that have shown the potential to overcome instances of binding site mutation-induced drug resistance. In theory, the PROTACs function is not mediated by binding to an active site for inhibition. Thus, PROTACs may be designed to engage with target proteins at residues that do not undergo the same degree of evolutionary pressure to mutate, compared to residues within an active site or catalytic domain.
References
1.Wang P, Zhou J. Curr Top Med Chem. 2018;18(16):1354–1356.
