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ML285 affects reactive oxygen species’ inhibition of pyruvate kinase M2.

Source

Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-.
2012 Aug 3 [updated 2013 May 8].

Author information

1
NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, 9800 Medical Center Drive, Rockville, MD, 20850.
2
Beth Israel Deaconess Medical Center, Department of Medicine-Division of Signal Transduction, Boston, MA 02115, USA.
3
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
4
Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
5
Novartis Institutes for Biomedical Research, Center for Proteomic Chemistry, Cambridge, MA 02139, USA.
6
Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology Cambridge, MA 02139, USA
7
Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
8
Department of Pharmacology, University of Toronto, Toronto, ON, M5G 1L7, Canada.

Excerpt

The ability of all cells to regulate levels of reactive oxygen species (ROS) is vital for controlling many aspects of proliferation and survival and we have discovered that pyruvate kinase M2 (PKM2) is important for cancer cell biology. PKM2 is directly oxidized on Cys358 to inhibit its catalytic activity, which allows for diversion of glucose-6-phosphate into the pentose phosphate pathway. This, in turn, allows the synthesis of NADPH, which is critical for generating reduced glutathione, necessary for ROS detoxification. In a cellular context, our PKM2 activator, ML285 protects the enzyme from oxidation by ROS and results in sensitization to oxidative stress and increased apoptosis.

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