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-RASG¹²V, 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.

K-RAS  /  Oncogenic mutants  /  Small-molecule degrader  /  Bifunctional compound  /  NEDD4-1  /  Ubiquitination  /  Degradation  /  Anticancer drug