The efficacy and selectivity of protein degrader drugs depend on their affinity to the target protein but also on the type of E3 ubiquitin ligase (E3) that is recruited to trigger proteasomal degradation. The arsenal of E3s that can be hijacked for targeted protein degradation (TPD) is still largely unexplored. Only about 2% of the more than 600 E3 ligases have been utilized to date. Exploiting additional E3 ligases that are selectively expressed in specific tissues or cell types, can broaden the applicability of TPD as a therapeutic modality.
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There are many drug target classes for which unwanted on-target pharmacology limits clinical application. Understanding E3 tissue expression across both healthy and diseased tissues enables a disease-directed TPD strategy based on all mapped E3 ligases. Using comparative analyses of expression patterns, one can identify selective pairings of E3 ligases with therapeutic targets of interest. Ligandability, Expression profile and Degradative activity (LED) criteria can be used to identify novel E3 ligases to match with clinically validated targets.
Fragment, structural, and virtual screening approaches have been used to identify ligands to a novel Cullin E3 ligase, which were successfully made into degraders. The co-crystal structure of an initial fragment hit with a Kd of > 1 mM was solved by X-ray crystallography revealing interactions within the degron binding pocket of this ligase. SBDD allowed improvement in affinity to approximately 30 uM and further cycles of in silico library design and synthesis further improved the potency to nM hits with good physical properties and low molecular weight. Degraders of multiple proteins including BRD4 and STAT3 were discovered using this novel E3 ligase binder.
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