Targeted protein degradation induced by small-molecule degraders has emerged as an attractive therapeutic approach to eliminate disease-relevant proteins from cells. Among the &gt;600 E3 ligases encoded by the human genome, cereblon (CRBN), a substrate recognition adaptor in the CRL4<sup>CRBN</sup> E3 ubiquitin ligase complex, plays a central role in targeted protein degradation applications. CRBN is a target of thalidomide and lenalidomide, which are clinically used in the treatment of hematopoietic malignancies and as ligands for targeted protein degradation. Despite expanding development of CRBN-targeting therapeutics, the endogenous structural motif recognized by the thalidomide-binding domain of CRBN has remained elusive. E3 ubiquitin ligase complexes select proteins for degradation through the recognition of degrons, specific amino acid sequences that are sufficient to promote ubiquitylation and degradation when embedded in a substrate. We thus hypothesized that synthetic ligands of CRBN, thalidomide and lenalidomide, mimic a naturally occurring degron of CRBN. Here, we will discuss our approach to discovering a degron for the thalidomide-binding domain of CRBN using a targeted protein degradation strategy as a functional readout.

Discovery of a degron for the thalidomide-binding domain of cereblon through a targeted protein degradation strategy

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ACS Fall 2022

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