Protein Degraders in Clinical Trials

Although the rule of 5 has served as a guiding principle for medicinal discovery scientists over the course of decades, it does not confine their exploration to molecules within the physicochemical property space. Protein degraders known as PROTACs, for instance, often possess properties that deviate from Lipinski’s rule, which characterizes molecules considered suitable for drug development. However, these molecules still exhibit bioavailability through oral administration, thanks to the functionality of linkers.

Another category of degraders, termed molecular glues, are modulators of E3 ligases and possess smaller molecular weights. They are created by leveraging the intrinsic degradation capability of E3 ligase ligand against specific proteins like IKZF1/3 and GSPT1. In contrast to PROTACs, molecular glues are discovered opportunistically and are restricted to a smaller subset of proteins. To broaden the applicability of this modality, a comprehensive and orthogonal screening approach is needed. This involves mapping the degradability of E3 ligand protein complexes and evaluating protein degradation across a compound library, rather than solely focusing on protein inhibition.