Metabolic reprogramming and redox control of cancer cells is vital for their proliferation, but also provides selective strategies for treating cancer. Increased generation of ROS and an intricate control of redox status in cancer cells relative to normal cells provide a basis of designing ROS-inducing anticancer agents. 2-deoxy-D-glucose (2-DG) is a hexokinase inhibitor and a ROS inducer with selective cytotoxicity to malignant cells relative to non-transformed cells and is undergoing clinical trials. This is due to vulnerability of cancer cells to reach lethal ROS levels above the antioxidant protective threshold. We recently discovered a D-xylose based small-molecule that has lower IC<sub>50 </sub>than 2-deoxy-D-glucose (2-DG) with the property of blocking metabolic activity and enhancing ROS. Mechanistic studies with Click chemistry suggest that our active compound, K8A block protein glycosylation in H1299 lung cancer cells. The National Cancer Institute also recently evaluated our compound in 60 cancer cell lines. K8A also activates AMPK and upregulates the tumor suppressor protein p53, underscoring its potential in reducing cancer cell proliferation. Importantly, metabolomic studies revealed that K8A disrupts altered metabolism in cancer.

Discovery of reactive oxygen species inducer for treatment of lung cancer

255th National Meeting (2018)

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