Discovery of a KLHL41 Ligand for Muscle Specific Protein Degradation PMID: 42191679

ADC Targets in Oncology

2026-04-10

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

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.

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.