Identification of activators for the M2 isoform of human pyruvate kinase Version 3

Matthew B Boxer  1 ,  Jian-kang Jiang  1 ,  Matthew G Vander Heiden  2  3 ,  Min Shen  1 ,  Henrike Veith  1 ,  Lewis C Cantley  4  5 ,  Craig J Thomas  1
Affiliations
  • 1. NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, MSC 3370 Bethesda, Maryland 20850
  • 2. Koch Institute at MIT, Cambridge, MA 02139, USA
  • 3. Dana Farber Cancer Institute, Boston, Massachusetts 02115
  • 4. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115
  • 5. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
PMID: 21735594
Abstract

The expression of human Pyruvate Kinase M2 (hPK-M2) in Cancer cells appears to be critical for tumor cell growth and proliferation in vivo. Because the PK-M2 isoform is expressed in all Cancer cells studied, it represents a target for drug development that could potentially enable tumor cells to return to a normal state of metabolism. If this novel strategy for targeting malignancy were successful, it would be applicable to diverse types of Cancer. The probes ML203 (CID-44543605), ML202 (CID-44246498), and ML170 (CID-4547230) are members of a series of highly specific allosteric activators for the tumor-specific isoform of human Pyruvate Kinase (M2 isoform). All three probes affect the cooperativity of phosphoenolpyruvate (PEP) binding, with little affect on adenosine diphosphate (ADP) binding, in a manner similar to Fructose-1,6-bisphosphate (FBP).

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