Abstract K-Ras mutations represent a most prevalent oncogenic alteration in human cancers. Despite of tremendous efforts, it remains a big challenge to develop inhibitors that can target the oncogenic K-Ras mutants, especially mutants without specific active or charged side chains such as K-Ras G12V . Here, taking advantage of our previous finding that Nedd4-1 is a bona fide 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 molecular glue to bind both the C2 domain of Nedd4-1 and an allosteric site of K-Ras to enhance Nedd4-1 and K-Ras interaction. Hence, our study presents a robust strategy to develop small-molecule degrader of K-Ras mutants, and also sheds light on the development of small-molecule degraders for H-Ras and N-Ras mutants.

Targeting oncogenic K-Ras mutants with a small-molecule degrader through Nedd4-1