Exploring Targeted Degradation Strategy for Oncogenic KRASG12C
Open accessAbstract
KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, KRAS G12C can be targeted by small-molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Our lead degrader successfully engaged CRBN in cells, bound KRAS G12C in vitro, induced CRBN/KRAS G12C dimerization, and degraded GFP-KRAS G12C in reporter cells in a CRBN-dependent manner. However, it failed to degrade endogenous KRAS G12C in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively poly-ubiquitinate endogenous KRAS G12C underlies the lack of activity. We discuss challenges for achieving targeted KRAS G12C degradation and proposed several possible solutions which may lead to efficient degradation of endogenous KRAS G12C.
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In KRASG12C mutants, small molecules covalently bound to the mutant cystine bind more readily to GDP-bound KRAS proteins; this binding reduces the affinity between GTP and KRAS, thus preventing GEF from catalyzing the replacement of GDP with GTP, thereby locking the KRASG12C mutant in an inactivated state.
“In KRASG12C mutants, small molecules covalently bound to the mutant cystine have been found to bind more readily to GDP-bound KRAS proteins. This binding reduces the affinity between GTP and KRAS, thus preventing GEF from catalyzing the replacement of GDP with GTP, thereby locking the KRASG12C mutant in an inactivated state.51”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [51]
These effects reduce affinity between GTP and KRAS, prevent GDP replacement by GTP through GEF catalysis, and lock KRAS mutants in inactive state.
“These effects reduce the affinity between GTP and KRAS, prevent GDP from being replaced by GTP through GEF catalysis, and ultimately lock KRAS mutants in an inactive state.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [51]
XY-4-88 (196) induces dimerization of CRBN-KRASG12C.
“One compound, named XY-4-88 (196), displayed the ability to induce dimerization of CRBN-KRASG12C (Table 4).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [51]
XY-4-88 fails to degrade endogenous KRASG12C and does not demonstrate a degradation-dependent phenotype.
“However, despite its covalent binding to KRASG12C, XY-4-88 failed to degrade endogenous KRASG12C and did not demonstrate a degradation-dependent phenotype.51”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [51]
Zeng et al. developed XY-4-88, a covalent PROTAC based on ARS-1620 and thalidomide as the CRBN-recruiting ligand.
“Zeng et al.124 initially developed a covalent PROTAC (XY-4-88) based on ARS-1620, a KRAS(G12C)-binding covalent warhead, and thalidomide as the CRBN-recruiting ligand124.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [124]
XY-4-88 degraded a GFP-KRAS(G12C) fusion protein in a non-catalytic manner but could not degrade untagged, endogenous KRAS(G12C).
“Although XY-4-88 was able to degrade a GFP–KRAS(G12C) fusion protein, albeit in a non-catalytic manner because it covalently bound the target, it could not degrade untagged, endogenous KRAS(G12C).”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [124]
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- Authors
- Zeng, M., Xiong, Y., Safaee, N., Nowak, R. P., Donovan, K. A., Yuan, C. J., Nabet, B., Gero, T. W., Feru, F., Li, L., Gondi, S., Ombelets, L. J., Quan, C., Jänne, P. A., Kostic, M., Scott, D. A., Westover, K. D., Fischer, E. S., & Gray, N. S.
- Affiliations
- Harvard University (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Westover, Kenneth D.
- Fischer, Eric S.
- Gray, Nathanael S.
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 27
- Issue
- 1
- Pages
- 19-31.e6
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- OpenAlex
- W2998586415
- Cited by
- 275
- References
- 72
- Citations by year
- 2026: 23 · 2025: 29 · 2024: 50 · 2023: 44 · 2022: 37 · 2021: 52 · 2020: 37 · 2014: 1
- FWCI
- 10.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Novartis
- Sanofi
- AbbVie
- Astellas Pharma US
- Boehringer Ingelheim
- Dana-Farber Cancer Institute
- Damon Runyon Cancer Research Foundation (CPRIT RP170373, DRR-50–18)
- Stand Up To Cancer (SU2C-AACR-DT17-15)
- Eli Lilly and Company
- Daiichi-Sankyo
- Pfizer
- Entertainment Industry Foundation
- American Cancer Society (PF-17-010-01-CDD)
- Takeda Pharmaceuticals U.S.A.
- American Association for Cancer Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- KRAS G12C, targeted protein degradation, PROTACs, cereblon, small molecule inhibitors, ubiquitination, pancreatic cancer, lung cancer, oncogenic KRAS, lead compound identification
- MeSH terms
- Antineoplastic Agents, Humans, Drug Design, Molecular Structure, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor, Protein Kinase Inhibitors, Proteolysis
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