Skip to main content
HHS Logo U.S. Department of Health & Human Services Divider arrow NIH logo National Institutes of Health Alt desc
Chemistry Technology

Development of an Activator of the Pyruvate Kinase Isoform M2 (PKM2)

Scientific Synopsis

Cancer cells exhibit altered metabolism and use of extracellular nutrients, providing a unique strategy to affect tumor growth. Tumors are known to import significantly higher amounts of glucose compared with normal tissue and use glucose’s carbons as cellular building blocks for proliferation. Associated with this enhanced glucose uptake, also known as the Warburg effect, the expression of the M2 isoform of pyruvate kinase is a factor contributing to biosynthesis and tumor growth. Scientists at NCATS developed TEPP-46 (ML265), a small molecule activator of PKM2 with an intriguing mechanism of action. PKM2 must adopt a tetrameric quaternary structure to be active, and TEPP-46 binds at the interface between the monomers, promoting tight protein binding. In addition, PKM2 activation impairs cancer proliferation by interfering with tumors’ anabolic metabolism. TEPP-46 constitutes a valuable molecular probe to study the downstream metabolic effects of PKM2 activation.

Image (a) shows an interaction between tetrameric PKM2 and TEPP-46. The four PKM2 monomers are represented in cartoon mode with different colors. The bound FBP and the activator molecules are colored black and red, respectively, and are shown as space-filling models in the middle. The interfaces between two monomers are indicated by dotted lines. Image (b) illustrates the interactions between TEPP-46 and the surrounding residues. The bound activator is colored yellow and represented by a ball-and-stick model. The residues from the two monomers that are involved in the interaction are colored green and cyan and labeled. Hydrogen bonds are shown by blue dashed lines with their distances indicated. (Reprinted with permission from Palsson-McDermott EM, et al. Pyruvate kinase M2 regulates HIF-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab. 2015;21(1):65–80. Copyright 2015 American Chemical Society.

Image (a) shows an interaction between tetrameric PKM2 and TEPP-46. The four PKM2 monomers are represented in cartoon mode with different colors. The bound FBP and the activator molecules are colored black and red, respectively, and are shown as space-filling models in the middle. The interfaces between two monomers are indicated by dotted lines. Image (b) illustrates the interactions between TEPP-46 and the surrounding residues. The bound activator is colored yellow and represented by a ball-and-stick model. The residues from the two monomers that are involved in the interaction are colored green and cyan and labeled. Hydrogen bonds are shown by blue dashed lines with their distances indicated. (Reprinted with permission from Palsson-McDermott EM, et al. Pyruvate kinase M2 regulates HIF-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages. Cell Metab. 2015;21(1):65–80. Copyright 2015 American Chemical Society.

Lead Collaborators

  • Craig J. Thomas, Ph.D., NCATS, NIH
  • Matthew G. Vander Heiden, Ph.D., Massachusetts Institute of Technology

Publications

Public Health Impact

One strategy to target cancer cells is to take advantage of their altered metabolic profiles, which distinguish them from other healthy cells. Developing a PKM2 activator allows scientists to intervene at a crucial crossroad of cancer metabolism, allowing for the selective and efficient killing of cancer cells. The development of such bioactive agent may lead to the discovery of a new effective, albeit less toxic, chemotherapeutic regimen.