Discovery of KRas G12C-IN-3 and Pomalidomide-based PROTACs as degraders of endogenous KRAS G12C with potent anticancer activity
Abstract
A series of KRAS G12C-targeting PROTACs (PROteolysis TArgeting Chimeras) were designed and synthesized based on KRas G12C-IN-3 (a KRAS G12C inhibitor) and pomalidomide as degraders of KRAS G12C with a molecular weight of < 900. Among them, compound KP-14 (m.w. = 852.16; tPSA = 174.53) showed the highest KRAS G12C-degrading capability in NCI-H358 cancer cells (DC 50≈1.25 μM). KP-14 bound to KRAS G12C through the acrylamide warhead and recruited the E3 ligase CRBN, causing rapid and sustained KRAS G12C degradation which led to suppression of MAPK signaling pathway in NCI-H358 cells. In addition, KP-14 selectively induced the degradation of KRAS G12C but not other KRAS isoforms such as G13D via PROTAC mechanism. Furthermore, KP-14 exhibited potent antiproliferative activity against NCI-H358 cancer cells and was able to suppress the formation of NCI-H358 tumor colonies. Collectively, this work suggests that KP-14 may serve as a tool compound for exploring the degradation of KRAS G12C by PROTAC strategy and deserve further investigation as a potential anticancer agent.
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KP-14 (198) exhibits exceptional KRASG12C degradation activity in NCI-H358 cells with a DC50 of 1.25 μM.
“Among the series, the degradant KP-14 (198) exhibited exceptional KRASG12C degradation activity in NCI-H358 cells, with a DC50 of 1.25 µM (Table 4).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [487]
KP-14 displays potent antiproliferative activity and inhibits tumor colony formation in NCI-H358 cells.
“Furthermore, KP-14 displayed potent antiproliferative activity and inhibited tumor colony formation in NCI-H358 cells.487”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [487]
KP-14 selectively degrades KRASG12C but not other KRAS mutants such as G13D through the protein-ubiquitin system.
“Mechanistic experiments revealed that KP-14 selectively degraded KRASG12C, but not other KRAS mutants such as G13D, through the protein-ubiquitin system.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [487]
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- Authors
- Li, L., Wu, Y., Yang, Z., Xu, C., Zhao, H., Liu, J., Chen, J., & Chen, J.
- Affiliations
- Southern Medical University (CN)
- Corresponding author
- Chen, Jianjun
- Venue
- Bioorganic Chemistry
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 117
- Pages
- 105447
- ISSN
- 0045-2068 (ISSN-L)
- OpenAlex
- W3205157000
- Cited by
- 48
- References
- 15
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 14 · 2023: 11 · 2022: 4 · 2014: 1
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Update notices
- erratum (2024-09-01)
- Open access
- closed
- Licence
- Locations
- Bioorganic Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- KRAS G12C, PROTACs, pomalidomide, protein degradation, MAPK signaling, NCI-H358 cells, anticancer agents, small molecule design
- MeSH terms
- Antineoplastic Agents, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Structure-Activity Relationship, Thalidomide, Tumor Cells, Cultured, Molecular Structure, Proto-Oncogene Proteins p21(ras), Cell Proliferation, Drug Discovery, Proteolysis
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