Abstract 1012: Discovery and synthesis of novel autophagy inhibitors with anti-proliferative activity in lung and pancreatic cancer cells

Abstract

Abstract Autophagy is an emerging therapeutic target in cancer chemotherapy. It is a regulated catabolic process that degrades damaged cellular proteins and organelles, and helps to maintain cellular homeostasis and biosynthesis during nutrient starvation, metabolic stress, oncogenic transformation, and in response to chemotherapeutic drugs. Recent studies using mouse genetic models of lung and pancreatic cancer reported dramatic tumor regressions when autophagy was ablated, either genetically or pharmacologically, in either the tumors or systemically in the mouse. These studies provide pre-clinical proof of principle that strategies to inhibit autophagy can be therapeutically efficacious in solid tumors. The autophagy inhibitors chloroquine (CQ) and hydroxychloroquine (HCQ) have single agent antiproliferative activity against human cancer cell lines, however low potency may limit their antitumor efficacy clinically. As part of our ongoing chemistry program to discover novel autophagy inhibitors, we synthesized a series of chloroquine analogs which retained the 4-aminoquinoline subunit and incorporated different substituted triazoles into the target structure. These compounds were tested for growth inhibition against H460, HCC827, H520 and H1703 human lung cancer cell lines, and BxPC3 pancreatic cancer cells. The most potent compound, EAD1, had IC50s ranging from 5.8 μM to 11 μM in the cells, and was 8-fold more potent than CQ and HCQ. EAD1 inhibited autophagy, as judged by the cellular accumulation of the autophagy-related autophagosome proteins LC3-II and p62, and induced apoptosis. The increases in LC3-II levels by the analogs were inversely correlated with their growth inhibitory IC50s, suggesting that autophagy blockade is closely linked to inhibition of cell proliferation. In contrast to HCQ, the cytotoxic actions of EAD1 were not reversible after a 24 hour treatment. Furthermore, the mechanism of action of EAD1 appears to partially differ from that of HCQ, including possible interactions with mTOR/TORC1-mediated pathways. EAD1 is a viable lead compound for evaluation of the anti-tumor activity of autophagy inhibitors in vivo. Citation Format: Juan Sironi, Lars Ulrik Nordstroem, Evelyn Aranda, Marina Shcherba, Roman Perez-Soler, Peng Wu, Edward L. Schwartz. Discovery and synthesis of novel autophagy inhibitors with anti-proliferative activity in lung and pancreatic cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1012. doi:10.1158/1538-7445.AM2015-1012