Dithiiranylmethyloxy azaxanthone shows potent anti-tumor activity via suppression of HER2 expression and HER2-mediated signals in HER2-overexpressing breast cancer cells.

Dithiiranylmethyloxy azaxanthone (CHO10), which was discovered by screening compounds in a reporter gene assay, inhibited the ESX-Sur2 interaction in a dose-dependent manner with potency similar to canertinib. The intervention of CHO10 during the ESX-Sur2 interaction caused down-regulation of both HER2 gene amplification and HER2 protein expression, which led to the attenuation of HER2-mediated downstream signal cascades and autocrine cell growth in SK-BR-3 cells, which are HER2 overexpressing breast cancer cells. The cell growth inhibitory activity of CHO10 was more potent in HER2-overexpressing breast cancer cells (AU-565, BT474 and SK-BR-3) than in HER2-negative cells (HEK293) and breast cancer cells (MCF-7) that express a basal level of HER2. Treatment with CHO10 in combination with tamoxifen sensitized BT474 cells, tamoxifen-resistant ER-positive breast cancer cell line, toward chemotherapeutic. The anti-tumor activity of CHO10 was validated by the significant reduction in tumor size of NCI-H460 or DLD-1 subcutaneously implanted xenograft tumors through treatment with 1mg/kg five times every other 2days.