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. 2025 Nov 5:297:117928.
doi: 10.1016/j.ejmech.2025.117928. Epub 2025 Jul 5.

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

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

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

Eunhye Jeon et al. Eur J Med Chem. .

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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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Taebo Sim reports financial support was provided by Ministry of Health & Welfare, Republic of Korea. Taebo Sim reports financial support was provided by National Research Foundation, Republic of Korea. Taebo Sim reports a relationship with Magicbullettherapeutics Inc that includes: equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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