Abstract NT-119: TARGET DISCOVERY OF NATURAL PRODUCT INSPIRED PHYLLANTHUSMINS FOR TREATMENT OF HIGH GRADE SEROUS OVARIAN CANCER

Abstract

Abstract BACKGROUND: High grade serous ovarian cancer (HGSOC) is a lethal gynecological malignancy with a need for new therapeutic agents. Many of the most widely used chemotherapeutic drugs are either derived from or are semi-synthetic derivatives of natural products. We developed potent synthetic analogs (PHYs) of the phyllanthusmin class inspired by prior natural product isolated from Phyllanthus poilanei Beille. MATERIALS & METHODS: HGSOC cell lines, OVCAR3 and OVCAR8, and non-tumorigenic controls, IOSE80 and FT33, were used in this study. Cytotoxicity assays included sulforhodamine B assay, and annexin X/PI staining and Western blotting for confirmation of apoptosis induction. A photo affinity labeling method was used to attach PHY analogs to solid phase support. Targets were isolated using a pulldown technique and mass spectrometry. CRISPR-Cas9 genome editing was used to knockout and confirm putative targets. RESULTS: The most potent analog, PHY34, has nanomolar potency in HGSOC cell lines in vitro and displayed cytotoxic activity through late-stage autophagy inhibition and activation of apoptosis. PHY34 was readily bioavailable through intraperitoneal administration in vivo where it significantly reduced HGSOC tumor burden. Targets were identified using photo affinity labeling-aided protein pulldown and mass spectrometry, and confirmed by generating knockout cell lines of targets. CONCLUSIONS: This class of compounds holds promise as a potential, novel chemotherapeutic approach and demonstrates the effectiveness of pleiotropically targeting autophagy and apoptosis as a viable strategy for combating high grade serous ovarian cancer. Citation Format: Alexandria N. Young, Steven Kurina, Andrew Huntsman, Rathnayake A. Rathnayake, Melissa Korkmaz, A. Douglas Kinghorn, Leslie Aldrich, Stephanie Cologna, James R. Fuchs, Joanna E. Burdette. TARGET DISCOVERY OF NATURAL PRODUCT INSPIRED PHYLLANTHUSMINS FOR TREATMENT OF HIGH GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-119.