RK447 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 1.15 uM.
RK447 effectively blocks RAS binding to the RAF isoforms with IC50 of 1.15 -7.52 uM.
RK447 inhibits RAS-driven cancer cell growth, RAS/RAF binding, and the subsequent activation of downstream signalling.
RK447 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.
RK447 suppresses tumour growth and inhibits RAS/MAPK signalling in in vivo models of RAS-driven cancers.
RK447 prevents BRAF inhibitor-induced paradoxical RAS signalling activation and exhibits antitumour activity against BRAF inhibitor-resistant melanoma.