Abstract LB-B28: Abietane natural products as novel therapeutics against solid tumors

Dysregulation of protein synthesis can lead to aberrant cellular proliferation and survival, a hallmark of cancer. Protein synthesis is a multistep process tightly controlled by specific translation factors. In eukaryotes, at the initiation point, the 43S preinitiation complex is formed by the association of several factors [eukaryotic initiation factor 2 (eIF2), GTP and methionyl initiator tRNA] with the 40S ribosomal subunit and the eukaryotic initiation factor 3 (eIF3). Over expression of eIFs has been reported in breast cancer, particularly in the most aggressive subtype, triple negative breast cancer (TNBC). More than one million global cases of breast cancer are diagnosed yearly and approximately 15% are characterized as triple negative breast cancer (TNBC), a subtype that lacks effective targeted therapy modalities. Recently, we generated a library of cell permeable abietane natural product derivatives (i.e. SJ6038) and showed that these compounds are more potent against TNBC over the estrogen receptor positive cellular models. These compounds were tagged with biotin for affinity enrichment and with a fluorescent chromophore to facilitate protein target(s) identification. A SILAC proteomics approach was used to distinguish specific binding targets from the non-specific ones. Gene Ontology analysis showed the targets identified were affiliated with regulation of protein synthesis. Ingenuity Pathway Analysis suggested that abietanes may exert their anticancer effects on critical biological pathways such as the eIF2, eIF4/p70S6K, and mTOR signaling pathways. Live cell experiments utilizing fluorescent abietane derivatives demonstrate that these probes localize to subsections of the ER, supporting the SILAC findings. Time of Exposure and Dose Response experiments further demonstrate that Abietane derivatives affect the eIF2 signaling axis. Using chemical biology and medicinal chemistry approaches, we show that abietane natural products preferentially promote cell death in TNBC cellular models by targeting the eIF2 signaling axis. These compounds will serve as unique chemical tools targeting the eIF2/eIF4 signaling axis and advance from hit- to lead for further preclinical development as a targeted therapy against aggressive solid tumors. Citation Format: Walter Lang, Taotao Ling, Jangsoon Lee, Naoto T. Ueno, Fatima Rivas. Abietane natural products as novel therapeutics against solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B28.