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<p>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.</p>

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Discovery of a KLHL41 Ligand for Muscle Specific Protein Degradation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Junhyeong Yim,
  • Jaeseok Lee,
  • Solbi Kim,
  • Jieun Choi,
  • Soyoung Yoon,
  • Hana Cho,
  • Sunbin Jung,
  • GaYeon Yoo,
  • Sanghee Lee,
  • Hankum Park,
  • Juyong Lee,
  • Jongmin Park

摘要

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.