Unlike conventional inhibition, induced disposal of proteins not only interferes with catalytic activity of POI but also eliminates any other associated scaffolding roles upon which cancer cells rely. PROTACs, by definition, are capable of eradicating target proteins from the cellular environment. Furthermore, recent advances in the TPD field indicate that exploitation of tissue-specific E3 ligases (e.g., KLHL41 in skeletal muscle, RNF112 in brain tissues, TRIM69 in testis, ASB9 in pancreas) or tumor-specific E3 ligases (e.g., TRIM50 and FBXO2) will significantly improve tumor-selective mode of PROTACs ( Also, application of TPD in oncology might overcome resistance mechanisms, such as overexpression of oncogenic proteins, and potentially reduce adverse effects compared with conventional inhibitor drugs due to the reported higher specificity of PROTACs. Thus, administration of relatively low doses might provide prolonged effects on the target protein compared with small molecule inhibition. Since PROTAC is an event-driven modality, when a noncovalent POI ligand is used in PROTAC design it can induce the degradation of the POI in a sub-stoichiometric manner. In this way, PROTAC technology has been widely applied against various disease-causing proteins with different biological roles and has demonstrated multiple advantages over conventional inhibitory strategies. Subsequent recruitment of these two entities in proximity induces ubiquitination of the POI and directs it to the cellular proteolytic machinery. PROTACs are composed of two ligands that bind to the POI and an E3 ligase, tethered together. Induced protein degradation by heterobifunctional PROTACs is designed to work by co-opting the natural cellular ubiquitination process.
Identification of biological processes and their functional effectors is invaluable not only to understand how our bodies function at the molecular level but also for the development of new therapeutic modalities. Different linker classes, designing principles and the dependency of PROTAC activity are discussed in greater detail elsewhere ( Therefore, while E3 ligase exploration is one option to develop selective degrader molecules, it is also advisable to employ E3 ligase ligands with multiple vector points and linker optimization strategies in order to induce potential protein:protein interactions between the target protein and E3 ligase complex. This study suggests that different forms of ternary complexes might determine isoform selectivity, although the orientation of recruited VHL ligand owing to different vector points of linker attachment still has to be considered as an important factor to achieve selective degradation. However, foretinib attached to the other end of the VHL ligand via the phenyl group, with a single atom difference in the linker length, displayed less activity toward p38α but it could significantly induce p38δ degradation.
When the p38 recruiting ligand, foretinib, was attached to one end of the VHL ligand via an amide bond, it could only degrade p38α. The resulting PROTACs displayed significantly different ability to induce the degradation of p38α and p38δ. Starting with the same pMAPK inhibitor (i.e., foretinib) and E3 ligase ligand, two PROTACs were generated that differed in their linker attachment sites in the VHL ligand. ) explored differential presentation of p38MAPK isoforms to VHL for potential PROTAC-mediated selective isoform degradation.
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