Bioactive small molecule development- PKM2 program

National Center For Advancing Translational Sciences

Investigators

Abstract

Pyruvate kinase is the penultimate step of glycolysis responsible for the conversion of phosphoenolpyruvate and ADP into pyruvate and ATP. There are 4 characterized pyruvate kinase isoforms (M1, M2, L and R) that differ in expression patterns, substrate affinity, enzymatic stability, catalytic efficiency and susceptibility to exogenous control. Activators of the M2 and R isoforms have been established and contribute to the biomedical community’s study of cancer cell metabolism and reticulocyte disorders, respectively. Recently, PK activators have been reported to increase the frequency of ATP/ADP cycling and calcium oscillations in pancreatic beta cells as a key element of insulin secretion. This discovery has led to an increased understanding of the role that glycolysis and oxidative phosphorylation play in diabetes pathophysiology. The goal of this study is to advance a pyruvate kinase activator to exploit these new discoveries as a means to modulate several metabolic disorders.