Abstract 5066: Chemoprevention of breast cancer by targeting glucose metabolism with HJC0152

Most mammalian cells use glucose as the primary fuel source, which is metabolized via glycolysis to pyruvate and further transferred into mitochondria for generating ATP through the Krebs cycle under normal condition. However, metabolism is characteristically reprogrammed in cancer cells or highly proliferative cells with a preferential ATP production through generating lactate by lactate dehydrogenase (LDH/LDHA), referred to as the Warburg effect or metabolic reprogramming toward anaerobic glycolysis. Efficient control of energy metabolism is the key to maintaining metabolic homeostasis, while disturbance in energy balance provokes diseases such as obesity, diabetes and cancer. However, the mechanisms underlying efficient energy metabolic homeostasis and breast cancer development are poorly understood. The transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) is activated downstream of many cytokines and growth factor receptors. STAT3-targeting genes and their functions vary depending on the cellular context, primarily in correlation with cell survival and proliferation. Recently, reports show that active STAT3 with phosphorylation at Y705 residue plays an important role in regulating energy metabolism via transcriptional induction of its well-recognized transcriptional target HIF-1α. HJC0152, a novel small-molecule glucose metabolism modulator, was proprietarily developed using a combination approach of structure-based drug design strategies and molecular modeling techniques in our attempt to develop orally bioavailable non-peptide STAT3 inhibitors for anticancer use. A panel of mammary epithelial cells and breast cancer cells treated with HJC0152 exhibited suppressed cell growth and induced apoptosis in vitro. Intriguingly, HJC0152 reduces glucose uptake and Glut1 protein level. In addition, HJC0152 treated BC cell line showed decreased protein level of glycolytic enzymes including HK2, PFKL, ALDOA, PDHK, PKM2, LDHA and important metabolism regulator HIF-1α in a time-dependent manner. Furthermore, HJC0152 has significant in vivo efficacy in reducing/preventing mammary tumor development in transgenic mouse models of estrogen receptor (ER)-negative breast cancer. These results provide a rationale to develop HJC0152 as a promising drug candidate and preventive therapy for breast cancer and other cancers with aberrant glucose metabolism. In addition, HJC0152 can serve as a molecular probing tool for elucidating the key factors driving the development of breast cancer in the context of metabolic dysregulation and diseases. This work was supported by grant R01CA226001 from the NIH/NCI. Citation Format: Hyejin Kim, Jiabin Dong, Lili Wang, Jimin Xu, Dan Zhang, Ruping Yan, Hao Zou, Haiying Chen, Xi Liu, Yun Zhu, Yu Xue, Jia Zhou, Qiang Shen. Chemoprevention of breast cancer by targeting glucose metabolism with HJC0152 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5066.