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Nov 01, 2012
 |  BC Innovations  |  Cover Story

Revving up glycolysis

A trio of papers has provided new hints into how best to use small molecule activators of pyruvate kinase M2 isozyme, a cancer metabolism enzyme present nearly universally across tumor types. Based on that research, activating the enzyme might be most effective in tumors with low levels of serine or oxygen.1-3

Pyruvate kinase occurs as two isoforms: pyruvate kinase M1 isozyme (PKM1) is expressed by most nonproliferative healthy tissues and PKM2 is mainly expressed in cancer cells. Both enzymes catalyze the final step in the energy-producing process of glycolysis.

The major difference between PKM1 and PKM2 is that PKM1 is constitutively active, whereas PKM2 has low basal activity that can be fine-tuned up or down by other metabolic and signaling pathways. Although both enzymes convert phosphoenolpyruvate into ATP and pyruvate, the final product of glycolysis, PKM2 does so at a much slower rate than PKM1.

In cancer cells expressing primarily PKM2, this results in a bottleneck in the glycolytic pathway that leads to the buildup of intermediate metabolites of glycolysis, which are believed to feed alternative biosynthetic pathways that enhance tumor cell growth and proliferation.

Based on these observations, researchers at Harvard Medical School hypothesized that activating PKM2 in cancer could reduce tumor growth. Indeed, a 2008 paper in Nature showed that replacing PKM2 in cancer cells with the more active PKM1 decreased tumor formation in mice.4

The challenge has been identifying small molecule activators of PKM2.

Now, a team from The Beatson Institute for Cancer Research and Astex Pharmaceuticals Inc. has identified a previously undescribed allosteric site on PKM2 that binds serine to boost activity of the enzyme.1 Independently, teams from the Massachusetts Institute of Technology and Agios Pharmaceuticals Inc. have each identified small molecule activators of PKM2 that bind a distinct allosteric site...

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