iMDK quarterhydrate, a potent PI3K inhibitor, is effective in inhibiting the growth factor MDK (also known as midkine or MK) while demonstrating suppression of non-small cell lung cancer (NSCLC). In combination with a MEK inhibitor, iMDK quarterhydrate demonstrates cooperative inhibition of NSCLC without causing harm to normal cells and mice [1].

iMDK (50-500 nM) quarterhydrate suppressed AKT phosphorylation in a dose-dependent manner in H441 lung adenocarcinoma cells after treatment for 72 h. In contrast, iMDK quarterhydrate robustly increases p-ERK [1]. Cell Viability Assay [1] Cell Line: H441 (lung adenocarcinoma; KRAS G12V ), H2009 (non-small cell carcinoma; KRAS G12A ), A549 (lung carcinoma; KRAS G12S ) and H520 (lung squamous cell carcinoma; KRAS WT ) Concentration: iMDK (2.5 μM) quarterhydrate and PD0325901 (0.5 μM) for H441 and H2009 cells iMDK (0.125 μM) quarterhydrate and PD0325901 (0.25 μM) for H520 cells iMDK (0.25 μM) quarterhydrate and PD0325901 (0.125 μM) for A549 cells Incubation Time: 72 hours Result: iMDK quarterhydrate alone did not inhibit cell viability of A549 cells, the combinatorial treatment of iMDK quarterhydrate with PD0325901 significantly inhibited that of A549 cells compared to the single treatment of PD0325901. Western Blot Analysis [1] Cell Line: H441 lung adenocarcinoma cells Concentration: 0-500 nM Incubation Time: 72 hours Result: Suppressed AKT phosphorylation in a dose-dependent manner. ERK1/2 phosphorylation was increased.

The combination treatment of iMDK ( (9 mg/kg/day; intraperitoneally injected with 100 μl) and PD0325901 (5 mg/kg; orally administered) effectively reduced lung tumor growth in a xenograft mouse model [1]. Animal Model: female BALB/c nude mice (6 week old) bearing H441 human lung cancer xenografts [1] Dosage: iMDK (9 mg/kg) quarterhydrate and PD0325901 (5 mg/kg) Administration: Intraperitoneally injected with 100 μL iMDK everyday and/or orally Result: Reduced significantly volume of the tumors derived from H441 lung adenocarcinoma cells after the combination treatment with iMDK quarterhydrate and PD0325901 compared to that of single compound in a xenograft mouse model.