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Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC
Fang Yang1, Yalei Wen1, Chaofan Wang1
1College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
European Journal of Medicinal Chemistry
|January 10, 2022
Summary
Researchers developed YF135, a novel reversible-covalent PROTAC, to target KRAS G12C. This new approach offers a potent strategy for cancer therapy by degrading the oncogene KRAS G12C.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- KRAS is a frequently mutated oncogene driving multiple cancers.
- Targeting KRAS G12C is a key strategy in cancer therapy.
- Existing PROTACs targeting KRAS G12C are irreversible, potentially limiting potency.
Purpose of the Study:
- To develop a novel, reversible-covalent PROTAC for KRAS G12C degradation.
- To evaluate the efficacy of the new PROTAC in cancer cells.
- To investigate the mechanism of action and reversibility of the PROTAC.
Main Methods:
- Development of YF135, a reversible-covalent PROTAC.
- Utilizing VHL-mediated proteasomal degradation pathway.
- Assessing KRAS G12C degradation and pERK signaling attenuation in H358 and H23 cells.
Main Results:
- YF135 is the first reversible-covalent PROTAC targeting KRAS G12C.
- YF135 induces rapid and sustained degradation of endogenous KRAS G12C.
- The degradation and pERK signaling attenuation by YF135 are reversible.
Conclusions:
- YF135 represents a promising new therapeutic strategy for KRAS G12C-driven cancers.
- Reversible PROTACs offer a potential advantage over irreversible ones.
- Further investigation into YF135's therapeutic potential is warranted.
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