Signal transducer and activator of transcription 3 (STAT3) is involved in the regulation of early embryonic development, angiogenesis, immune response, cell proliferation, and apoptosis. Additionally, STAT3 overexpresses in many cancers.

As a result, it becomes an attractive therapeutic target for various cancer treatment studies. However, despite much intensive researches contribute to the discovery of small molecules targeting STAT3, there is still no candidate clinical use in oncology. Thus, it is urgent to an orally bioavailable agent targeting STAT3.

In this article, we will introduce a potent and orally active STAT3 inhibitor with an enhanced anticancer profile than Stattic, HJC0416.

Firstly, in vitro, HJC0416 inhibits the proliferation of both ER-positive or negative breast cancer cells with IC₅₀ values of 1.76 µM and 1.97 µM, respectively. However, it displays a marked antiproliferative effect against pancreatic cancer cell line AsPC1 and Panc-1 with IC₅₀ values of 40 nM and 1.88 µM, respectively. In MDA-MB-231 breast cancer cells, HJC0416 inhibits cell growth and induced apoptosis accompanying cellular morphological changes. Besides, in MDA-MB-231 cells after transient transfecting with pSTAT3-Luc vector, HJC0416 decreases the STAT3 promoter activity by approximately 51%. While Stattic only decreases the STAT3 promoter activity by 39%. Furthermore, HJC0416 has a comparable potency in downregulating STAT3 protein production and phosphorylation at Tyr-705 site when compares with Stattic. Additionally, it also induces cleaved caspase-3 and downregulated cyclin D1 levels in MDA-MB-231 cells.

In vivo, in the MDA-MB-231 triple-negative breast cancer murine xenograft model. HJC0416 shows a 67% decrease in tumor volume as compared to the control mice after 7 days of treatment. Similarly, HJC0416 hydrochloride also significantly reduces tumor volume at a dose of 100 mg/kg by 46%.

As a result, i.p.route appeared to have a better reduction of tumor volume. It is also noteworthy that HJC0416 does not show significant signs of toxicity at a dose of 100 mg/kg.

In conclusion, as a potent and promising Stat3 inhibitor, HJC0416 is a promising anti-tumor agent for breast cancer research.