MT477 acts in tumor cells as an AURKA inhibitor and strongly induces NRF-2 signaling.

Background: The novel compound thiopyrano [2,3-c]quinoline (MT477) has been shown to exhibit antitumor activity in both in vitro and in vivo studies. The present study examined the expression levels of 10,000 genes and how they changed after MT477 treatment in three cancer cell lines: H226, MDA231 and MiaPaCa-2. Materials and Methods/

Results: Molecular function analysis revealed changes in genes involved in cell death, cell-cycle progression and cellular growth and proliferation in all three cancer cell lines. Canonical pathway analysis showed the involvement of the NRF2-mediated oxidative stress response, glucocorticoid, p53, RXR-VDR, G(1)/S checkpoint regulation, ERK, SAPK/JNK and JAS/Stat signaling. Analysis of 234 kinases and phosphatases using a kinase inhibition assay demonstrated a strong inhibitory effect for MAPK14 (104 ± 2%), AMPK A2/B1/G1 (89%) and FGR (83 ± 2%). AURKA was inhibited at 77 ± 1%. MiaPaCa-2 tumor xenograft studies showed a 49.5 ±1 4.8% inhibitory effect in mice treated with 100 μg/kg MT477 compared to untreated mice (p=0.0021).

Conclusion: MT477 induces molecular mechanisms related to cell death, survival, and inhibition of cellular growth in vitro and in vivo.