Targeted kinase degradation via the KLHDC2 ubiquitin E3 ligase

Chemically induced protein degradation is a powerful strategy for perturbing cellular biochemistry. The pre-dominant mechanism of action for protein degrader drugs involves an induced proximity between the cellular ubiquitin-conjugation machinery and a target. Unlike traditional small molecule enzyme inhibition, targeted protein degradation can clear an undesired protein from cells. We demonstrate here the use of peptide li-gands for Kelch-like homology domain-containing protein 2 (KLHDC2), a substrate adapter protein and mem-ber of the cullin-2 (CUL2) ubiquitin ligase complex, for targeted protein degradation. Peptide-based bivalent compounds that can induce proximity between KLHDC2 and target proteins cause degradation of the tar-geted factors. The cellular activity of these compounds depends on KLHDC2 binding. This work demon-strates the utility of KLHDC2 for targeted protein degradation and exemplifies a strategy for the rational design of peptide-based ligands useful for this purpose.