By Reto Horst
Heterobifunctional chimeric degraders are a class of ligands that recruit target proteins to E3 ubiquitin ligases to drive compound-dependent protein degradation. Critical to the mechanism of action is the formation of a ternary complex between the target, degrader and E3 ligase to promote ubiquitination and subsequent degradation. However, limited insights into ternary complex structures exist to date. Here, we present the use of protein-detected NMR spectroscopy to characterize degrader-mediated ternary complexes of Bruton’s tyrosine kinase and cellular inhibitor of apoptosis 1 (cIAP1), one of the most widely co-opted E3s. In combination with orthogonal biophysical and structura l studies, the NMR results reveal new insights from unique ternary complex structures and show that increased ternary complex stability or rigidity does not always correlate with increased degradation efficiency. Implications to drug design will be discussed in the presentation.