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Pyruvate Kinase M2 Activators for the Treatment of Cancer

Posted Dec 07 2010 7:00pm

Description of Invention:
NIH investigators have discovered a series of small compounds with the potential to treat a variety of cancers as well as hemolytic anemia. Contrary to most cancer medications, these molecules can be non-toxic to normal cells because they target a protein specific to the metabolic pathways in tumors, thus representing a significant clinical advantage over less-specific chemotherapeutics.

The invention described here is a series of small molecules that activate pyruvate kinase (PK) isoform M2. PK-M2 is a critical metabolic enzyme that is affected in all forms of cancer. Inactivation of PK-M2 leads to a buildup of metabolic intermediates inside the cell. Tumor cells require a buildup of metabolic intermediates in order to undergo rapid cell growth and proliferation. Hence, activation of PK-M2 in tumor cells may prevent the buildup of metabolic intermediates and thereby stall tumor cell proliferation or destroy the tumor cells. Further, while in normal post-embryonic cells only PK isoforms R, L, or M1 are active, in all tumors only PK-M2 is active. So, PK-M2 activation would affect only tumor cells, and small-molecule PK-M2 activators may not be toxic to healthy cells.

This invention discloses the use of two new small molecule pharmacophores that can activate PKM2 through the allosteric site: 3-oxo-3,4-dihydro-2H-benzo [b] [1,4] oxazine-7-sulfonamides, and 2-oxo-1,2,3,4-tetrahydroquinoline-6-sulfonamides.

  • Therapeutic developments for various cancers
  • Diagnostic assays for various cancers
  • Regulation of embryonic stem cell proliferation

  • Small molecule (series of analogs can be derived in search of improved performance)
  • Target a select group of cells (Cancerous cells)

Development Status:
  • Pre-clinical; no animal data
  • In vitro data available

Matthew B Boxer (NHGRI)
Douglas S Auld (NHGRI)
Craig J Thomas (NHGRI)
Min Shen (NHGRI)

Patent Status:
HHS, Reference No. E-120-2010/0
US, Application No. 61/329,158 filed 29 Apr 2010

Relevant Publication:
  1. Jiang JK et al. Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg Med Chem Lett. 2010 Jun 1;20(11):3387-3393. [ PubMed: 20451379 ]
  2. Boxer MB et al. Evaluation of substituted N,N'-diarylsulfonamides as activators of the tumor cell specific M2 isoform of pyruvate kinase. J Med Chem. 2010 Feb 11;53(3):1048-1055. [ PubMed: 20017496 ]

Licensing Status:
Available for licensing

Collaborative Research Opportunity:
The NIH Chemical Genomics Center (NCGC), National Human Genome Research Institute, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize these pyruvate kinase M2 activators. Please contact Dr. Matthew Boxer at for more information.

Cancer - Therapeutics

For Licensing Information Please Contact:
Steven Standley Ph.D.
NIH Office of Technology Transfer
6011 Executive Blvd. Suite 325,
Rockville, MD 20852
United States
Phone: 301-435-4074
Fax: 301-402-0220

Ref No: 2202

Updated: 12/2010

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