KRA-533, a potent KRAS agonist, directly targets the GTP/GDP binding pocket within the KRAS protein, inhibiting GTP cleavage. This inhibition leads to the buildup of constitutively active GTP-bound KRAS, which subsequently activates both apoptotic and autophagic cell death pathways specifically in cancer cells.

KRA-533 (10 μM; 48 hours; HCC827 cells) enhances KRAS activity to a greater extent[1]. KRA-533 (0~15 μM; 48 hours; H157 cells) enhances KRAS activity in a dose-dependent manner, which is associated increased levels of pERK, ratio of active caspase 3/procaspase 3 and PARP cleavage, leading to apoptotic cell death[1]. KRA-533 (10 μM; 10 days; H292 cells) mediates cell growth suppression than those without KRAS mutation. KRA-533 (5~15 μM) can directly bind to WT, G12C, G12D and G13D mutant KRAS proteins. KRA-533 activates WT KRAS to increase its activity in a dose-dependent manner. KRA-533 further enhances the activities of active KRAS mutants[1]. Western Blot Analysis[1]Cell Line: HCC827 cells Concentration: 10 μM Incubation Time: 48 hours Result: Enhanced KRAS activity to a greater extent. Apoptosis Analysis[1]Cell Line: H157 cells Concentration: 0~15 μM Incubation Time: 48 hours Result: Enhanced KRAS activity in a dose-dependent manner, which was associated increased levels of pERK, ratio of active caspase 3/procaspase 3 and PARP cleavage, leading to apoptotic cell death.

KRA-533 (0~30 mg/kg; 28 days) suppresses tumor growth in a dose-dependent manner in lung cancer mutant KRAS xenografts and induces apoptosis and autophagy in tumor tissues in a dose-dependent manner[1]. KRA-533 shows optimal therapeutic index between 7.5 mg/kg and 30 mg/kg doses[1]. Animal Model: Nu/Nu nude mice[1]Dosage: 0~30 mg/kg Administration: I.p. Result: Suppressed tumor growth in a dose-dependent manner in lung cancer mutant KRAS xenografts and induced apoptosis and autophagy in tumor tissues in a dose-dependent manner.