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Development of a Novel Separase Inhibitor, Sepin-1 for Breast Cancer Therapy

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Technical Report,15 May 2017,14 May 2018

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Baylor College of Medicine Houston United States

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Current treatment options for advanced, metastatic, highly heterogeneous, and refractory breast cancer BC tumors are extremely limited, contributing to most of the BC-related deaths in USA and around the world primarily due to drug-resistance, and drug-related side effects and toxicities. The goal of this project is to develop a new class of drugs for the treatment of refractory BC that are safe and effective with the least side effects. Separase, an enzyme that cleaves the chromosomal cohesin complex during mitosis, is overexpressed in more than 60 percent of BC and 50 percent of TNBC, and 65 percent of Luminal-B BC tumors and its overexpression strongly correlates with aneuploidy, high incidence of relapse, metastasis, and a lower 5-year overall survival rate. Separase is an oncogene, and overexpression of Separase induces aneuploidy, genomic instability, mammary tumorigenesis, and intratumoral heterogeneity in mice. We posit that modulation of Separase enzymatic activity constitutes a new therapeutic strategy for targeting resistant, Separase-overexpressing aneuploid tumors, particularly the hard-to-treat TNBC. We hypothesize that pharmacologic modulation of Separase enzymatic activity constitutes a new therapeutic strategy for targeting Separase-overexpressing aneuploid heterogeneous tumors. We further hypothesize that by decreasing Separase activity to a therapeutically useful degree of inhibition by Sepin compounds, we will effectively reprogram the Separase-overexpressing tumors and that partial Separase inhibition will selectively eliminate Separase-overexpressing tumor cells addicted to elevated Separase expression while sparing normal cells, and thereby preventing aneuploidy and aneuploidy-associated tumor heterogeneity.

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  • Medicine and Medical Research

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