Elucidating the mode of action of the abietanes to develop potential therapeutic agents_supplement

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PROJECT ABSTRACT Over expression of eukaryotic initiation factors (eIFs) has been reported in various human diseases including breast cancer (BC). Our objective is to develop tool compounds based on the abietane natural products to selectively target eIFs. Approximately 15-20% breast cancer cases are characterized as triple negative breast cancer (TNBC), a subtype that lacks effective targeted therapy modalities,1 and is often plagued with dysfunctional eIFs expression.2 Therefore, there is a need to discover new chemical matter that could selectively targeted TNBC to reduce mortality rates associated with this disease. We have shown that abietane natural product derivatives (SJ38) significantly reduce protein synthesis and target eIF2/eIF4 signaling axis in TNBC cellular models. We discovered that a) SJ38 selectively inhibits cancer cell viability at the low micromolar range (<10μM) while not affecting non-cancerous mammary epithelial cell viability or signaling, b) SJ38 significantly reduces the expression of regulatory factors involved in protein synthesis, and c) Stable isotope labeling with amino acids in cell culture (SILAC) proteomics provided Gene Ontology analysis that SJ38 mainly targeted protein synthesis and Ingenuity Pathway Analysis suggested that SJ38 exerts its anticancer effects primarily through the eIF2, and eIF4/p70S6K signaling pathway. Our long-term goal is to elucidate SJ38 molecular mechanism in TNBC focusing on translational control. Our study addresses a gap in knowledge to discover new therapeutic agents and biological targets to potentially treat TNBC. We hypothesize that SJ38 reduces breast cancer progression and sensitizes cells to therapy via translational control. We propose the following specific aims: 1) Develop a novel synthetic strategy to access a series of diverse abietane derivatives to facilitate structure activity relationship (SAR), and target engagement studies. 2) Determine the biological properties of the generated compounds as protein synthesis modulators and their capability to inhibit proliferation and migration in TNBC cellular models. 3) Identify the mechanism by which the abietanes target cancer cellular models. IMPACT: Results from the proposed studies will provide critical knowledge towards the development of targeted therapeutic strategies needed for the successful treatment of human diseases including cancer.