HJC0416 hydrochloride, a potent, orally active inhibitor of STAT3, exhibits a superior anticancer profile compared to Stattic. It stands out as a promising agent for breast cancer research.

HJC0416 hydrochloride demonstrates inhibitory effects on the proliferation of ER-positive and triple-negative (ER-negative) breast cancer cells, with IC 50 values of 1.76 μM and 1.97 μM, respectively. It exhibits significant antiproliferative activity against pancreatic cancer cell lines AsPC1 and Panc-1, with IC 50 values of 40 nM and 1.88 μM. At concentrations of 1-10 μM over 48 hours, HJC0416 hydrochloride restricts cell growth and induces apoptosis, alongside morphological changes in MDA-MB-231 breast cancer cells. It reduces STAT3 promoter activity by approximately 51% at 5 μM over 24 hours, compared to a 39% reduction by stattic (HY-13818) in MDA-MB-231 cells transfected with a pSTAT3-Luc vector. Furthermore, within 12 hours at 1-10 μM, HJC0416 matches the efficacy of Stattic in diminishing STAT3 protein levels and phosphorylation at the Tyr-705 site, and it enhances cleaved caspase-3 production while reducing cyclin D1 levels in MDA-MB-231 cells. Analysis reveals induced apoptosis in MDA-MB-231 cells at 1-10 μM after 48 hours and a decrease in p-STAT3 phosphorylation and cyclin D1 expression at 1, 5, and 10 μM after 12 hours.

HJC0416 hydrochloride, administered via intraperitoneal injection at 10 mg/kg for 7 days, demonstrated a significant reduction in tumor volume by 67% compared to control mice. When given orally at 100 mg/kg for 14 days, it notably decreased tumor volume by 46%. The intraperitoneal route was more effective in reducing tumor volume. Importantly, HJC0416 hydrochloride exhibited no significant signs of toxicity at these dosages. This study was conducted on mice implanted with MDA-MB-231 cells, highlighting HJC0416's potential as an antitumor agent in the triple-negative breast cancer murine xenograft model.