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,ta...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.展开更多
基金supported by the National Key R&D Program(2022YFC2804100 to Xianming Deng,China)the National Natural Science Foundation of China(82273037 to Hong-Rui Wang+5 种基金22025702,82021003,82151211 and 92253303 to Xianming Deng32070761 to Taoling Zeng)the Natural Science Foundation of Fujian Province(2022J05006 to Taoling Zeng,China)the Fundamental Research Funds for the Chinese Central Universities(20720230070 to Taoling Zeng,China)the Project“111”sponsored by the State Bureau of Foreign Experts and Ministry of Education of China(#BP2018017)the New Cornerstone Science Foundation through the XPLORER PRIZE(To Xianming Deng).
文摘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.
