Amy Reyes, “SIMMPYRA1 and SIMMPYRA2 Promote the Regression of Triple Negative Breast Cancer via Selective Inhibition of Signal Transducer and Activator of Transcription 3”
Mentor: Avik Roy, Biological Sciences
Poster #157

Triple-negative breast cancer (TNBC) is the most devastating form of breast cancer with poor life expectancy. Multiple mutations in steroid hormone receptors make these cells unresponsive to steroid hormones and a series of other pharmacological agents having a similar fused ring structure. As a result, current therapeutic options are limited for the treatment of TNBC tumors. Here we report that two benzothiophene analogs named SIMMPYRA1(SIM1) and SIMMPYRA2 (SIM2) promote the apoptosis of TNBC cells, but not normal mammary epithelial cells. We have discovered these two compounds by an in-silico high throughput screening study of 32 novel compounds against STAT3, performed chemical synthesis, validated binding with STAT3 by protein thermal shift assay, evaluated their STAT3 inhibitory role by an array strategy against all different activated STAT3 proteins followed by the confirmation with GFP reporter and electrophoretic mobility shift assay (EMSA). A gene array of 66 STAT3-dependent genes, and a protein array of 40 STAT3-dependent proteins, combining results with STRING network analysis and then a confirmatory ELISA analysis revealed that both SIM1- and SIM2 markedly downregulated several STAT3-dependent targets primarily IL6 and RANTES in TNBC cells. Finally, by conducting LDH release, TUNEL, and AnnexinV/propidium iodide staining assay, we concluded that low doses (CT50 ~ 20nM) of these two molecules induced apoptosis in multiple TNBC cells.