KRA-533 is an effective KRAS agonist that targets the GTP/GDP binding pocket within the KRAS protein, inhibiting GTP cleavage. This leads to accumulation of the active GTP-KRAS form, promoting apoptosis and autophagic death in cancer cells.

In HCC827 cells, KRA-533 (10 μM, 48 hours) significantly enhanced KRAS activity [1].
In H157 cells, the enhancement of KRAS activity by KRA-533 (0-15 μM, 48 hours) exhibited a dose-dependent effect. This effect was associated with elevated pERK levels, an increased ratio of active caspase 3/pro-caspase 3, and PARP cleavage, ultimately inducing apoptosis [1].
In H292 cells, KRA-533 (10 μM, 10 days) exhibited stronger growth inhibitory effects on KRAS-mutant cells compared to cells without KRAS mutations [1]. KRA-533 (5-15 μM) directly bound to wild-type (WT) KRAS protein as well as G12C, G12D, and G13D mutant KRAS proteins [1]. KRA-533 enhanced WT KRAS activity in a dose-dependent manner and further increased the activity of constitutively active KRAS mutants [1].

In the KRAS mutant lung cancer xenograft model of Parazacco spilurus subsp. spilurus, KRA-533 (0-30 mg/kg, 28 days) administered via intraperitoneal injection demonstrated dose-dependent inhibition of tumor growth and dose-related induction of apoptosis and autophagy processes in tumor tissues [1]. KRA-533 exhibited optimal therapeutic indices within the dose range of 7.5 mg/kg to 30 mg/kg [1].