Targeting glycolytic aldolase: an Achilles heel in cancer metabolism

Increased nutrient uptake is a major hallmark of cancer and correlates with a poor survival rate. Many of the oncogenic events that drive cancer development influence metabolism by increasing glucose and glutamine uptake while other genetic events and processes also influence metabolism without increased nutrient uptake. Together these events reprogram metabolism away from catabolic metabolism and promote the anabolic pathways necessary for cell growth and proliferation. Glycolysis/gluconeogenesis is the key metabolic pathway that provides intermediates for cell growth and proliferation. We have targeted the central glycolytic enzyme aldolase which reversibly cleaves fructose-bisphosphate into triose-Ps by screening a 135 000 compound library for inhibitors of aldolase activity. One compound, UM0112176, allosterically inhibits aldolase activity at micromolar levels (IC50 ≈ 5 μM) and is cytotoxic to cancer cells (EC50 ≈ 5 μM) grown in glucose only, in glutamine only, and in complete cell culture media. The compound has good selectivity when tested against normal tissue culture cells exhibiting a 10–20-fold therapeutic window. Intracellular targeting of aldolase by UM0112176 is consistent with aldolase substrate/product accumulation depending on the direction of the glycolytic flux. The mechanism of action by UM0112176 is surprising as the compound not only targets the important metabolic role of aldolase but also impacts its moonlighting activities in F-actin polymerization, and novel activities related to ROS production and DNA repair. The elucidation of the essential role played by aldolase in metabolism and associated moonlighting activities, as revealed through the mechanism of action by UM0112176, will be the topic of the conference. L6.2