[HTML][HTML] ML265: A potent PKM2 activator induces tetramerization and reduces tumor formation and size in a mouse xenograft model

J Jiang, MJ Walsh, KR Brimacombe… - Probe Reports from …, 2013 - ncbi.nlm.nih.gov
J Jiang, MJ Walsh, KR Brimacombe, D Anastasiou, Y Yu, WJ Israelsen, BS Hong, W Tempel…
Probe Reports from the NIH Molecular Libraries Program [Internet], 2013ncbi.nlm.nih.gov
Cancer cells have altered metabolic processes compared to normal differentiated cells and
the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this
aberrant metabolism. The M1 isoform is a highly active enzyme typically expressed in
muscle and brain tissue, the alternatively spliced M2 variant is considerably less active and
expressed in many tumors studied to date. This report describes the use of the PKM2
activator, ML265, and details some of the biophysical, ex vivo and in vivo activity of this …
Cancer cells have altered metabolic processes compared to normal differentiated cells and the expression of the M2 isozyme of pyruvate kinase (PKM2) plays an important role in this aberrant metabolism. The M1 isoform is a highly active enzyme typically expressed in muscle and brain tissue, the alternatively spliced M2 variant is considerably less active and expressed in many tumors studied to date. This report describes the use of the PKM2 activator, ML265, and details some of the biophysical, ex vivo and in vivo activity of this compound. ML265 induces the more active tetrameric state of PKM2 and the X-ray co-crystal structure shows that the activator binds at the dimer-dimer interface between two subunits of PKM2. This compound was tested in a H1299 mouse xenograft model and showed significant reduction in tumor size, weight, and occurrence with no apparent toxicity over the 7-week experiment.
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