Discovery of a KLHL41 Ligand for Muscle Specific Protein Degradation

Despite the recent advancement of proteolysis-targeting chimera (PROTAC) development, they remain predominantly dependent on two E3 ligases, CRBN and VHL, which are ubiquitously expressed in all types of cells. Recently, efforts to discover tissue-specific E3 ligase ligands get attention as a promising strategy to enable tissue-specific protein degradation and avoid off-target tissue effects. Advancing this line of research, we discover a ligand of KLHL41, a muscle-specific E3 ligase, through virtual screening. Building on the KLHL41 ligand, we develop KBD-1, a muscle-specific BRD4-targeting PROTAC with micromolar activity. To enhance degradation efficiency, we employ a two-body kinetic strategy, resulting in the covalent PROTAC cKBD-1, which achieves sub-nanomolar activity. cKBD-1 demonstrates muscle-specific BRD4 degradation through KLHL41 recruitment both in vitro and in vivo. Moreover, the KLHL41 ligand enables AR-targeting PROTAC development, demonstrating its broad applicability. These findings highlight the potential of KLHL41 as a platform for tissue-specific protein degradation and its applicability in therapeutic development. PROTACs rely mainly on ubiquitous E3 ligases, limiting tissue selectivity. Here, the authors identify a ligand of muscle specific E3 ligase KLHL41 and develop a covalent PROTAC (cKBD-1) that enables potent, muscle-specific protein degradation in vitro and in vivo.