Abstract 3805: Anticancer agent HJC0416 inhibits the growth of breast cancer xenografts via downregulating STAT3 signaling

Abstract

Abstract Signal transducers and activators of transcription (STATs) play important roles in regulating the expression of genes activated during tumorigenesis. Particularly, STAT3 has been shown to contribute significantly in breast carcinogenesis and is often overexpressed in primary breast tumors. Increased STAT3 transcriptional activity is correlated with ER-negative phenotype in breast cancer cell lines and in primary invasive ductal breast carcinomas. Therefore, STAT3 emerges as a promising target for breast cancer treatment and prevention. We have designed, synthesized and screened a series of novel STAT3 inhibitors utilizing fragment-based drug design strategy. A number of small molecules with novel scaffolds have been discovered with low-micromolar to nanomolar potency in inhibiting the proliferation of various human breast cancer and pancreatic cancer cells. The identified compound HJC0416 significantly suppresses STAT3 promoter activity and STAT3 phosphorylation, reduces total STAT3 protein expression, induces cell growth arrest and early apoptosis in triple-negative breast cancer cell line MDA-MB-231. HJC0416 also demonstrated a better efficacy in suppressing the growth of MDA-MB-231 breast xenograft tumors via intraperitoneal and oral administrative routes, with remarkably improved aqueous solubility and less toxicity than the lead compounds. We further demonstrated that p70S6K and MAPK pathways mediate the inhibitory effects from HJC0416 via downregulating RPS6, PDCD4 and EEF2K proteins. In conclusion, the new anticancer agent HJC0416 inhibits the growth of breast cancer xenografts via suppressing STAT3 expression and its phosphorylation. Citation Format: Ailian Xiong, Haijun Chen, Zhengduo Yang, Guoshuai Cai, Lili Wang, Chunyong Ding, Grace G. Xu, Christopher Wild, Na Ye, Ivan P. Uray, Jia Zhou, Qiang Shen. Anticancer agent HJC0416 inhibits the growth of breast cancer xenografts via downregulating STAT3 signaling. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3805. doi:10.1158/1538-7445.AM2014-3805