RK440 is a specific small-molecule RAS/RAF inhibitor that specifically binds to CRAF RAS binding domain (RBD), allosterically disrupts RAS/RAF binding, exhibits potent HRAS/CRAF binding inhibition in ELISA with IC50 of 1.41 uM.
RK440 effectively blocks RAS binding to the RAF isoforms with IC50 of 1.41-12.55 uM.
RK440 inhibits RAS-driven cancer cell growth, RAS/RAF binding, and the subsequent activation of downstream signalling.
RK440 effectively inhibits cell growth of RAS-driven cancer cells with a wide variety of RAS mutations, as follows: CCRF-CEM (KRASG12D), PANC-1 (KRASG12D), SHP-77 (KRASG12V), SW620 (KRASG12V), HL-60 (NRASQ61L), Hs578T (HRASG12D), MOLT-4 (NRASG12C), THP-1 (NRASG12D), MIA PaCa-2 (KRASG12C), DLD-1 (KRASG13D), and HCT116 (KRASG13D) cells, with IC50 values ranging from 0.74 to 4.73 uM.
RK440 suppresses tumour growth and inhibits RAS/MAPK signalling in in vivo models of RAS-driven cancers
RK440 binding induces negative allosteric modulation of RAF RBD conformation, thereby preventing RAS/RAF interaction.
RK440 prevents BRAF inhibitor-induced paradoxical RAS signalling activation and exhibits antitumour activity against BRAF inhibitor-resistant melanoma.