Targeted Degradation of Oncogenic KRAS G12C by VHL-Recruiting PROTACs
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Abstract
High Resolution Image Download MS PowerPoint Slide KRAS is mutated in ∼20% of human cancers and is one of the most sought-after targets for pharmacological modulation, despite having historically been considered “undruggable.” The discovery of potent covalent inhibitors of the KRAS G12C mutant in recent years has sparked a new wave of interest in small molecules targeting KRAS. While these inhibitors have shown promise in the clinic, we wanted to explore PROTAC-mediated degradation as a complementary strategy to modulate mutant KRAS. Herein, we report the development of LC-2, the first PROTAC capable of degrading endogenous KRAS G12C . LC-2 covalently binds KRAS G12C with a MRTX849 warhead and recruits the E3 ligase VHL, inducing rapid and sustained KRAS G12C degradation leading to suppression of MAPK signaling in both homozygous and heterozygous KRAS G12C cell lines. LC-2 demonstrates that PROTAC-mediated degradation is a viable option for attenuating oncogenic KRAS levels and downstream signaling in cancer cells.
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LC-2 is a PROTAC that fuses the G12C selective inhibitor MRTX849 with the E3 ubiquitin ligase VHL.
“LC-2 is one such PROTAC that fuses the G12C selective inhibitor MRTX849 with the E3 ubiquitin ligase VHL [76].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [76]
The Discussion identifies LC-2 as a PROTAC that couples the KRASG12C-selective inhibitor MRTX849 to a VHL ligand. The claim is imprecise in saying LC-2 fuses MRTX849 with the VHL E3 ligase itself: the ligand recruits VHL; the ligase is not a component fused into LC-2. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPROTAC technologies are designed to induce selective degradation of KRAS proteins through recruitment of E3 ubiquitin ligases and subsequent proteasomal destruction.
“PROTAC (proteolysis-targeting chimera) technologies are designed to induce selective degradation of KRAS proteins through recruitment of E3 ubiquitin ligases and subsequent proteasomal destruction [61,62,63,64].”
From Precision Targeting of KRAS-Mutant Cancers: Beyond G12C Toward G12D and Pan-RAS Therapeutic Strategies (2026) · cites this paper as [61]
Treatment with LC-2 resulted in the proteasome-dependent depletion of mutant KRAS and the reduction in downstream signaling.
“Treatment with LC-2 resulted in the proteasome-dependent depletion of mutant KRAS and the reduction in downstream signaling [76].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [76]
LC-2 (197) is the first PROTAC molecule capable of degrading endogenous KRASG12C.
“Crews’s group reported the development of LC-2 (197) in 2020, the first PROTAC molecule capable of degrading endogenous KRASG12C (Table 4).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [486]
LC-2 binds covalently to KRASG12C through the MRTX849 warhead and recruits the E3 ligase VHL.
“LC-2 binds covalently to KRASG12C through the MRTX849 warhead and recruits the E3 ligase VHL.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [486]
LC-2 induces rapid and sustained degradation of KRASG12C and inhibits MAPK signaling in various cancer cell lines with homozygous and heterozygous KRASG12C.
“Experiments showed that LC-2 induced rapid and sustained degradation of KRASG12C, inhibiting MAPK signaling in various cancer cell lines with both homozygous and heterozygous KRASG12C.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [486]
LC-2's ability to overcome increased KRASG12C expression suggests KRASG12C degraders may be more effective than inhibitors alone in maintaining suppression of downstream signaling.
“Notably, LC-2’s ability to overcome increased KRASG12C expression suggests that KRASG12C degraders may be more effective in maintaining suppression of downstream signaling than inhibitors alone.486”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [486]
LC-2 combines adagrasib and a ligand for the E3 ligase VHL, enabling depletion of KRASG12C protein and attenuation of proliferation in KRASG12C-mutant cell lines.
“This compound combines adagrasib and a ligand for the E3 ligase VHL, enabling depletion of KRASG12C protein and thus attenuation of cellular proliferation in KRASG12C-mutant cell lines187.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [187]
Covalent KRASG12C PROTACs are not catalytic, and their advantages over covalent KRASG12C inhibitors are unclear.
“Covalent inhibitors that target KRASG12C in its GDP-bound “OFF” state have been successfully converted into PROTACs but such covalent PROTACs are not catalytic, and it is unclear what advantages they possess beyond covalent KRAS-G12C inhibitors (52, 53).”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [52]
LC-2 is the first degrading agent capable of degrading endogenous KRAS G12C; it covalently binds KRAS G12C and recruits E3 ligase VHL to rapidly induce KRAS G12C degradation and inhibits MAPK signaling in KRAS G12C mutated cancer cell lines.
“Bond et al. reported the first degrading agent LC-2 which is capable of degrading endogenous KRAS (G12C) [83]. It covalently binds to KRAS (G12C) and recruits E3 ligase VHL to rapidly induce KRAS (G12C) degradation and inhibits MAPK signaling in KRAS (G12C) mutated cancer cell lines.”
From Targeting KRAS mutant cancers: from druggable therapy to drug resistance (2022) · cites this paper as [83]
PROTACs that covalently bind the POI lose the ability to turn over and act iteratively.
“PROTACs that covalently bind the POI lose the ability to turn over and act iteratively55”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [55]
LC-2 engaged endogenous KRAS(G12C), induced its poly-ubiquitylation and degraded it via the 20S proteasome.
“LC-2 was able to engage endogenous KRAS(G12C), induce its poly-ubiquitylation and degrade it via the 20S proteasome.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [55]
Bond et al. developed LC-2, a covalent VHL-KRAS(G12C) PROTAC based on MRTX849 and a VHL ligand.
“Bond et al.55 developed a covalent VHL–KRAS(G12C) PROTAC (LC-2), based on the MRTX849 KRAS(G12C)-targeting warhead and a VHL ligand.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [55]
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Ligandability of E3 Ligases for Targeted Protein Degradation Applications
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The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells
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Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs)
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Self-citationIntegrative Modeling of PROTAC-Mediated Ternary Complexes
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Peptide-based PROTAC degrader of FOXM1 suppresses cancer and decreases GLUT1 and PD-L1 expression
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Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC
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PROTAC degraders as chemical probes for studying target biology and target validation
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PROTAC therapy as a new targeted therapy for lung cancer
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KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance
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Targeting Small GTPases and Their Prenylation in Diabetes Mellitus
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Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein
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Kano, Y. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27135796
- Authors
- Bond, M. J., Chu, L., Nalawansha, D. A., Li, K., & Crews, C. M.
- Affiliations
- Yale University (US)
- Corresponding author
- Crews, Craig M.
- Venue
- ACS Central Science
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-07-08
- Volume
- 6
- Issue
- 8
- Pages
- 1367-1375
- ISSN
- 2374-7943 (ISSN-L)
- 2374-7951
- PMC
- PMC7453568
- OpenAlex
- W3040830058
- Cited by
- 450
- References
- 51
- Citations by year
- 2026: 58 · 2025: 83 · 2024: 85 · 2023: 79 · 2022: 65 · 2021: 63 · 2020: 15 · 2014: 1
- FWCI
- 18.58
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- Locations
- ACS Central Science (publishedVersion, other-oa)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by-nc-nd)
- Funders
- U.S. Department of Health and Human Services (F31CA232477, R35197589, 5T32GM067543)
- American Cancer Society
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- KRAS G12C, PROTACs, targeted protein degradation, VHL E3 ubiquitin ligase, adagrasib, MAPK signaling, oncogenic KRAS, covalent inhibitors, cancer therapy
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