2. Academic Validation
  3. Discovery of a KLHL41 Ligand for Muscle Specific Protein Degradation

Discovery of a KLHL41 Ligand for Muscle Specific Protein Degradation

  • Nat Commun. 2026 May 26;17(1):4551. doi: 10.1038/s41467-026-73252-4.
Junhyeong Yim # 1 2 3,  Jaeseok Lee # 1 2 4,  Solbi Kim # 1 2 4,  Jieun Choi # 5,  Soyoung Yoon 6,  Hana Cho 6 7,  Sunbin Jung 6,  GaYeon Yoo 8 9,  Sanghee Lee 8 9,  Hankum Park 10 11 12,  Juyong Lee 13 14 15 16,  Jongmin Park 17 18 19
Affiliations

Affiliations

  • 1 Department of Chemistry, Kangwon National University, Chuncheon, Republic of Korea.
  • 2 Multidimensional Genomics Research Center, Kangwon National University, Chuncheon, Republic of Korea.
  • 3 Division of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
  • 4 Institute for Molecular Science and Fusion Technology, Kangwon National University, Chuncheon, Republic of Korea.
  • 5 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.
  • 6 Department of Dental Sciences, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
  • 7 Institute for Data Innovation in Science, Seoul National University, Seoul, Republic of Korea.
  • 8 Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
  • 9 KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul, Republic of Korea.
  • 10 Department of Dental Sciences, School of Dentistry, Seoul National University, Seoul, Republic of Korea. [email protected].
  • 11 Institute for Data Innovation in Science, Seoul National University, Seoul, Republic of Korea. [email protected].
  • 12 Dental Multiomics Center, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea. [email protected].
  • 13 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea. [email protected].
  • 14 College of Pharmacy, Seoul National University, Seoul, Republic of Korea. [email protected].
  • 15 Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, Seoul, Republic of Korea. [email protected].
  • 16 Arontier co., Seoul, Republic of Korea. [email protected].
  • 17 Department of Chemistry, Kangwon National University, Chuncheon, Republic of Korea. [email protected].
  • 18 Multidimensional Genomics Research Center, Kangwon National University, Chuncheon, Republic of Korea. [email protected].
  • 19 Institute for Molecular Science and Fusion Technology, Kangwon National University, Chuncheon, Republic of Korea. [email protected].
  • # Contributed equally.
PMID: 42191679 DOI: 10.1038/s41467-026-73252-4
Abstract

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.

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