Destructive relationships - Novel proteomic technique helps to define protein degradation complexes.
The most common therapeutic strategy for drug development is the inhibition of enzymatic activity, which has many challenges, including the relatively limited protein repertoire available to be targeted (only 20-25% of all proteins have been identified as drug targets). Importantly, this ignores the other protein functions, such as scaffolding, that play central roles in phenotypic outcomes and disease.
PROteolysis TArgeting Chimeras (PROTACs) have recently emerged as a novel therapeutic strategy, providing a completely new avenue to drug development, garnering enormous attention from Pharma and Academics as a unique tool that can facilitate previously intractable targets. PROTACs are bifunctional drugs that link target proteins to the degradation machinery of cells, thereby degrading targeted proteins instead of just inhibiting them. They have already shown promise across many disorders, including neurodegenerative, viral infections, immune disorders and cancer.
In work recently published in Molecular Cell, Reichermeier et. al., comprehensively describe the key mechanisms regulating CRL4, an important E3 ligase, that is commonly used as the degradation target of PROTAC based drugs. Using IonOpticks Aurora Series columns, the team discovered previously unknown interaction kinetics, stoichiometries and dynamic nature of interchangeable multiprotein complexes that are associated with CRL4. This important work identifies key substrate receptors that could feasibly enhance the degrader potency of this system, opening the doors to better therapeutics.
PIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network. Molecular Cell. 2020 Mar 5;77(5):1092-1106.e9. doi: https://doi.org/10.1016/j.molcel.2019.12.013
Reichermeier KM, Straube R, Reitsma JM, Sweredoski MJ, Rose CM, Moradian A, den Besten W, Hinkle T, Verschueren E, Petzold G, Thomä NH, Wertz IE, Deshaies RJ, Kirkpatrick DS.