R162

R162 is an inhibitor of glutamate dehydrogenase 1 (GDH1; IC₅₀ = 23 µM).¹ It decreases intracellular fumarate levels and increases the production of mitochondrial reactive oxygen species (ROS) in human H1299 lung and MDA-MB-231 breast cancer cells. R162 (10-40 µM) inhibits proliferation in a panel of human cancer cell lines, including lung, breast, and leukemia cells, but not normal human HaCaT keratinocytes, MRC-5 lung fibroblasts, or foreskin fibroblasts. It reduces tumor growth and intratumoral GDH1 activity in an H1299 mouse xenograft model when administered at a dose of 20 mg/kg. R162 also reduces liver metastasis in a liver kinase B1-deficient lung cancer patient-derived xenograft (PDX) mouse model when administered at the same dose.²

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1. Jin, L., Li., D., Alesi, G.N., et al. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell 27(2), 257-270 (2015).

2. Jin, L., Chun, J., Pan, C., et al. The PLAG1-GDH1 axis promotes anoikis resistance and tumor metastasis through CamKK2-AMPK signaling in LKB1-deficient lung cancer. Mol. Cell 69(1), 87-99 (2018).