Abstract P2-06-13: A novel small molecule JMX0293 inhibits the growth of triple-negative breast cancer via suppressing STAT3 and inducing apoptosis

Approximately 30-40% of breast cancer cases are estrogen receptor negative (ENBC), including the most aggressive triple-negative subtype (TNBC) which spread early and recur frequently with a poor prognosis. ENBCs do not respond to selective ER modulators such as tamoxifen or aromatase inhibitors, and therefore, there is an urgent need of non-ER-based therapies for ENBC and TNBC. We recently developed a novel small molecule JMX0293 based on our lead drug candidate HJC0152. Both HJC0152 and JMX0293 were able to suppress cell proliferation of both ER + (MCF-7, T-47D) and ER - (MDA-MB-231 and MDA-MB-468) breast cancer cell lines in a dose-dependent manner, with significantly lower toxicity against normal mammary epithelial cells (MCF-10A) in vitro . JMX0293 exhibited moderately improved anti-proliferative effects against highly invasive TNBC cell line MDA-MB-231 and ER + breast cancer cell line MCF-7 with IC 50 values of 0.92 and 2.24 μM, respectively. JMX0293 was also demonstrated to induce apoptosis of MDA-MB-231 cells dose-dependently. Mechanistically, JMX0293 inhibited STAT3 phosphorylation at Tyr705 residue, leading to the down-regulation of Bcl-2 and upregulation of apoptotic proteins including Bax, cleaved-caspase 3 and cleaved-PARP. In addition, JMX0293 reduced the ratio of Bcl-2 to Bax. In vivo, JMX0293 treatment for 2 weeks at a dose of 10 mg/kg significantly suppressed the growth of TNBC xenograft tumors in mice with minimal impact on general health and body weight. Our results suggest that JMX0293 induces TNBC cell apoptosis and contributes to its anti-proliferative effect through inhibiting transcription factor STAT3, and JMX0293 could be further characterized and optimized for developing a promising therapeutic for treating ENBC and TNBC. This work was supported by grant (R01 CA231150) from the NIH/NCI. Citation Format: Dong J, Xu J, Kim H, Zhou J, Shen Q. A novel small molecule JMX0293 inhibits the growth of triple-negative breast cancer via suppressing STAT3 and inducing apoptosis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-06-13.