XMU-MP-9 is bifunctional, specific small molecule K-RAS mutants degrader, facilitates NEDD4-1-mediated ubiquitination and degradation of various oncogenic K-RAS mutants.
XMU-MP-9 could induce decrease of endogenous K-RASG12V protein levels in SW620 cells as early as 12 h treatment and reached a maximum effect at 36 to 48 h.
XMU-MP-9 exhibits potent effect on inhibiting growth of NEDD4-1+/+ SW620 cells in 2-D culture and 3-D soft agar in comparison to NEDD4-1−/− SW620 cells, also induces NEDD4-1-dependent decrease of endogenous K-RASG12V protein levels.
XMU-MP-9 primarily assists NEDD4-1 in attaching ubiquitin to K128 of K-RASG12V.
XMU-MP-9 interacted with both K-RASG12V and NEDD4-1 with similar binding affinities (Kd = 18.4 and 25.4 nM).
XMU-MP-9 promotes ubiquitination and degradation of various K-RAS mutants such as G12D, G12C, G12S, G13V, G13D, and Q61H via lysosomal pathway, but not H-RAS or N-RAS mutants.
XMU-MP-9 inhibits proliferation and anchorage-independent growth of K-RAS mutant harboring cancer cells.
XMU-MP-9 (40 mg/kg once or twice daily via tail vein injection) suppresses tumor development of K-RAS mutant harboring cancer cells in vivo.