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.
Lead Collaborators
- Craig J. Thomas, Ph.D., NCATS, NIH
- Matthew G. Vander Heiden, Ph.D., Massachusetts Institute of Technology
Publications
- Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MA, Sheedy FJ, Gleeson LE, van den Bosch MW, Quinn SR, Domingo-Fernandez R, Johnston DG, Jiang J-k, Israelsen WJ, Keane J, Thomas C, Clish C, Vander Heiden M, Xavier RJ, O'Neill LA. 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. doi: 10.1016/j.cmet.2014.12.005
- Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A, Yang H, Mattaini KR, Metallo CM, Fiske BP, Courtney KD, Malstrom S, Khan TM, Kung C, Skoumbourdis AP, Veith H, Southall N, Walsh MJ, Brimacombe KR, Leister W, Lunt SY, Johnson ZR, Yen KE, Kunii K, Davidson SM, Christofk HR, Austin CP, Inglese J, Harris MH, Asara JM, Stephanopoulos G, Salituro FG, Jin S, Dang L, Auld DS, Park HW, Cantley LC, Thomas CJ, Vander Heiden MG. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol. 2012;8(10):839–47. Erratum in: Nat Chem Biol. 2012;8(12):1008.
- Walsh MJ, Brimacombe KR, Anastasiou D, Yu Y, Israelsen WJ, Hong BS, Tempel W, Dimov S, Veith H, Yang H, Kung C, Yen KE, Dang L, Salituro F, Auld DS, Park HW, Vander Heiden MG, Thomas CJ, Shen M, Boxer MB. ML265: A potent PKM2 activator induces tetramerization and reduces tumor formation and size in a mouse xenograft model. Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information; 2012 Mar 16 [updated 2013 May 8].
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.