Small molecule-induced targeted protein degradation (TPD) has emerged as a powerful new modality that enables development of therapies against targets long thought to be undruggable. Structure-based design has proven to be instrumental in accelerating the development of new proteolysis targeting chimeras (PROTACs) and molecular glues that induce TPD.<br/>This is primarily exemplified by compounds targeting the von Hippel Lindau (VHL) E3 ligase receptor which are now routinely optimized using a battery of structural and biophysical approaches to potentiate the molecular interactions within small molecule-induced ternary complexes.<br/>In contrast, the structural and biophysical tools available for high-throughput optimisation of degraders that utilise other E3 ligase receptors, such as cereblon (CRBN) are significantly restricted by the demanding requirements for stable recombinant protein in high quantities.<br/>Here, we present a new approach that significantly expands the toolbox available to investigate molecular interactions of E3 ligase-targeting modalities, enabling in-depth structural and biophysical studies to drive degrader optimization.

Expanding the toolbox for structural and biophysical characterization of degraders

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