The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC
Abstract
KRAS is the most frequently mutated oncogene and plays a predominant role in driving initiation and progression of multiple cancers. Attempts to degrade the oncogene KRAS G12C with PROTAC strategy have been considered as an alternative strategy to combate cancers. However, the irreversible PROTACs may compromise the substoichiometric activity to decrease the potency. Herein, we report the development of YF135, the first reversible-covalent PROTAC capable of recruiting VHL mediated proteasomal degradation of KRAS G12C. YF135 induces the rapid and sustained degradation of endogenous KRAS G12C and attenuates pERK signaling in H358 and H23 cells in a reversible manner.
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In the citing paper
“Although YF135’s degradation activity was not as robust as LC-2’s, this study still offers a promising new direction for the development of reversible-covalent degraders.488”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [488]
In the citing paper
“The antiproliferative activity of YF135 was also observed to be favorable in both tumor cell lines, with IC50 values of 153.9 nM and 243.9 nM, respectively.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [488]
In the citing paper
“YF135 demonstrated optimal degradation activity in both H358 and H23 cells, inducing KRASG12C protein degradation with DC50 values of 3.61 µM and 4.53 µM, respectively.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [488]
In the citing paper
“Recently, the Lu group made a breakthrough by creating the first reversible-covalent PROTAC, YF135 (199), which is based on cyanacrylamide and linked to a VHL ligand scaffold using MRTX849 (Table 4).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [488]
Citations
Cites
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A., & Shokat, K. M. (2013) · Nature · doi:10.1038/nature12796 · Cited by 2,557
The Clinical KRAS(G12C) Inhibitor AMG 510 Drives Anti-Tumour Immunity
Canon, J., Rex, K., Saiki, A. Y., Mohr, C., Cooke, K., Bagal, D., Gaida, K., Holt, T., Knutson, C. G., Koppada, N., et al. (2019) · Nature · doi:10.1038/s41586-019-1694-1 · Cited by 2,277
A Comprehensive Survey of Ras Mutations in Cancer
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RAS Proteins and Their Regulators in Human Disease
Simanshu, D. K., Nissley, D. V., & McCormick, F. (2017) · Cell · doi:10.1016/j.cell.2017.06.009 · Cited by 1,943
The Ras-RasGAP Complex: Structural Basis for GTPase Activation and Its Loss in Oncogenic Ras Mutants
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Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486
Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356
Hallin, J., Engstrom, L. D., Hargis, L., Calinisan, A., Aranda, R., Briere, D. M., Sudhakar, N., Bowcut, V., Baer, B. R., Ballard, J. A., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1167 · Cited by 1,304
Acquired Resistance to KRAS G12C Inhibition in Cancer
Awad, M. M., Liu, S., Rybkin, I. I., Arbour, K. C., Dilly, J., Zhu, V. W., Johnson, M. L., Heist, R. S., Patil, T., Riely, G. J., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2105281 · Cited by 1,247
Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor
Janes, M. R., Zhang, J., Li, L.-S., Hansen, R., Peters, U., Guo, X., Chen, Y., Babbar, A., Firdaus, S. J., Darjania, L., et al. (2018) · Cell · doi:10.1016/j.cell.2018.01.006 · Cited by 1,172
Cited by
Sorted by citations
Items 101–112 of 112
BindingDB Entry 50019814: Annual review of KRAS inhibitors in 2022.
BindingDB (2024) · UC San Diego · doi:10.7270/q2sx6jm1
BindingDB Entry 50019525: PROTACS: A technology with a gold rush-like atmosphere.
BindingDB (2024) · UC San Diego · doi:10.7270/q2hq4488
BindingDB Entry 50021145: Annual review of PROTAC degraders as anticancer agents in 2022.
BindingDB (2025) · UC San Diego · doi:10.7270/q2805771
BindingDB (2025) · UC San Diego · doi:10.7270/q280579x
BindingDB Entry 50018797: A bibliometric analysis of PROTAC from 2001 to 2021.
BindingDB (2024) · UC San Diego · doi:10.7270/q28p64s7
BindingDB (2026) · UC San Diego · doi:10.7270/q27p94b7
BindingDB Entry 50018614: Design, synthesis and biological evaluation of KRAS
BindingDB (2024) · UC San Diego · doi:10.7270/q2w66r1k
Tang, J., Cheng, Z., Xie, T., Zhuang, Y., Hu, H., Li, C., Wang, H., Feng, C., & Tu, C. (2026) · Biomarker Research · doi:10.1186/s40364-026-01032-9
Metadata
- Authors
- Yang, F., Wen, Y., Wang, C., Zhou, Y., Zhou, Y., Zhang, Z.-M., Liu, T., & Lu, X.
- Affiliations
- Jinan University (CN)
- Corresponding author
- Liu, Tongzheng
- Lu, Xiaoyun
- Venue
- European Journal of Medicinal Chemistry
- Publisher
- Elsevier BV
- Published
- 2022-02
- Volume
- 230
- Pages
- 114088
- ISSN
- 0223-5234 (ISSN-L)
- OpenAlex
- W4206601451
- Cited by
- 109
- References
- 38
- Citations by year
- 2026: 16 · 2025: 29 · 2024: 27 · 2023: 21 · 2022: 15
- FWCI
- 7.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- European Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12C, PROTACs, VHL, proteasomal degradation, PERK signaling, H358 cells, H23 cells, KRAS inhibitors
- MeSH terms
- Humans, Mutation, Neoplasms, Oligopeptides, Oncogenes, Proto-Oncogene Proteins p21(ras), Carcinogenesis
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