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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]
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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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