Targeting oncogenic K-RAS mutants with small-molecule degrader XMU-MP-9 through NEDD4-1
Year: 2025
Type: article
Abstract: K-RAS mutations represent a most prevalent oncogenic alteration in human cancers. Despite tremendous efforts, it remains a big challenge to develop strategies that specifically target the oncogenic K-RAS mutants. Here, taking advantage of our previous finding that NEDD4-1 is an E3 ubiquitin ligase for wild-type RAS proteins, we developed a compound XMU-MP-9 that can promote ubiquitination and degradation of various K-RAS mutants including K-RAS G12V , and significantly inhibit proliferation and tumor development of K-RAS mutant harboring cells. Mechanistically, XMU-MP-9 acts as a bifunctional compound to bind the C2 domain of NEDD4-1 and an allosteric site of K-RAS to enhance NEDD4-1 and K-RAS interaction, and to induce a conformational change of NEDD4-1/K-RAS complex to allow NEDD4-1 targeting K128 of K-RAS for ubiquitination. Hence, our study presents an effective way to degrade K-RAS mutants to prevent tumor development. Binding of XMU-MP-9 to the complex of NEDD4-1/K-RAS mutant promotes NEDD4-1-mediated ubiquitination of K-RAS mutant.
Source: Acta Pharmaceutica Sinica B
Institution: Xiamen University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,600
Funders: National Natural Science Foundation of China, Ministry of Education of the People's Republic of China, Natural Science Foundation of Fujian Province, State Administration of Foreign Experts Affairs, Key Technologies Research and Development Program, National Key Research and Development Program of China, Fundamental Research Funds for the Central Universities
OpenAlex ID: W4413097210