HexoKinase II Inhibitors
(Licensed to Calithera Biosciences, Inc.)
Hexokinase II catalyzes the 1st step in glycolytic pathway (which is overexpressed in human cancer), and its overexpression correlates with poor patient survival. The use of aerobic glycolysis for ATP generation is unique to tumor cells. HK II plays a key role in generation of metabolites important for tumor growth and survival, including lactate, ATP, NADPH, glutathione. HK II is Important in suppression of apoptosis; HK II-bound to mitochondria is key for survival (anti-apoptosis) of tumor cells. Potent, specific HK II inhibitors with pharmaceutical properties are lacking.
Utilizing TTP Translational Technology®, potent inhibitors of human HK1 and HK2 enzymes have been identified that inhibit of tumor cell growth (ovarian, lung, pancreas) and induce apoptosis in vitro. Inhibition of cellular HK2 enzyme causes a decrease in intracellular glucose 6-phosphate levels. Inhibition of HK2 leads to decreases in lactate, ATP and glutathione production in tumor cells; important metabolites for tumor cell growth and survival. Mitochondria membrane potential is decreased and redistribution of mitochondria-bound HK2 protein to the nucleus is observed. Inhibition of mTOR pathway is seen without inducing autophagy. Targeting accelerated glycolysis in cancer cells is a new promising modality for treatment of cancer.
Inhibition of glycolysis can be done without significant side effects, and such treatment will be additive to most known cancer therapies. HK2 enzyme inhibitors have been identified and human tumor xenograft studies in models of ovarian, pancreatic and lung cancers are ongoing.