2. Academic Validation
  3. KRASG12D selective VHL-PROTAC with sparing KRASWT and other KRAS mutants

KRASG12D selective VHL-PROTAC with sparing KRASWT and other KRAS mutants

  • Eur J Med Chem. 2025 Jul 5:297:117928. doi: 10.1016/j.ejmech.2025.117928.
Eunhye Jeon 1,  Chan Kim 1,  Minjoo Ko 1,  Taeyul K Kim 2,  Juhyeon Bae 1,  Jae Won Oh 3,  Kwang Pyo Kim 3,  Han Sang Kim 4,  Taebo Sim 5
Affiliations

Affiliations

  • 1 Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 FOUR Project, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 2 Department of Internal Medicine, Graduate School of Medical Science, Brain Korea 21 FOUR Project, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 3 Department of Applied Chemistry, Institute of Natural Science, Kyung Hee University, Yongin, Republic of Korea; Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, Republic of Korea.
  • 4 Department of Internal Medicine, Graduate School of Medical Science, Brain Korea 21 FOUR Project, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 5 Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 FOUR Project, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Biomedical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea; Graduate School of Clinical Drug Discovery & Development, Yonsei University College of Medicine, Seoul, Republic of Korea; Clinical Candidate Discovery & Development Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: TBSIM@yuhs.ac.
PMID: 40651134 DOI: 10.1016/j.ejmech.2025.117928
Abstract

KRASG12D is the most prevalent KRAS mutant in various cancers. We report the KRASG12D selective PROTAC, CH091138 (6), identified through SAR studies. 6 selectively degrades exogenous and endogenous KRASG12D but not KRASWT or Other KRAS mutants. Furthermore, global proteomic analysis shows that KRAS is most significantly downregulated in AsPC-1 cells. Mechanistic studies reveal that the degradation depends on the VHL-mediated ubiquitin-proteasome system. The binding site of 6 was identified by NMR studies, and docking studies explain 6-mediated interaction between KRASG12D and VHL leads to KRASG12D selectivity. 6 suppresses the proliferation of AsPC-1 cells and the growth of colon Cancer patient-derived organoids (PDOs) harboring KRASG12D but not PDOs with KRASWT. Notably, 6 reduces tumor growth in an AsPC-1 xenograft mouse model. Collectively, we report KRASG12D selective PROTAC and propose potential hypotheses for the selectivity. Also, our study reveals that PROTAC-mediated degradation of KRASG12D is an attractive anti-cancer strategy.

Keywords

KRAS; Mutant selective; Pancreatic cancer; Selective KRAS G12D degrader; Targeted protein degradation; VHL PROTAC.

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