Pyruvate Kinase M2 Activators for the Treatment of Cancer


This technology describes a series of small-molecule activators of the pyruvate kinase M2 isoform (PK-M2).

Pyruvate kinase (PK) is a critical metabolic enzyme that catalyzes the last step of the glycolytic pathway. It exists in several isoforms with different patterns of tissue expression. One isoform, PK-M2, is expressed in cells with a high rate of nucleic acid synthesis, including most tumors, which makes this enzyme an attractive target for cancer therapy. PK-M2 can occur in either a tetrameric form or a dimeric form in proliferating cells; a high tetramer to dimer ratio leads to energy production, while a low ratio channels metabolites into synthetic processes. In tumor cells, oncoproteins induce dimerization of PK-M2, resulting in the inactive form of the protein and allowing synthesis of building blocks for cell proliferation. Activation of PK-M2 in these cells may prevent the buildup of metabolic intermediates and thereby stall tumor cell proliferation. Further, after embryonic development PK-M2 expression is primarily restricted to tumor cells, so specific activators of PK-M2 would be expected to affect only tumor cells, and would be less likely to be toxic in normal tissues.

Investigators at the National Center for Advancing Translational Sciences have discovered a series of small molecules that specifically activate the PK-M2 isoform and that may be useful for the treatment of cancer. These compounds are based upon a substituted thieno[3,2-b]pyrrole[3,2-d]pyridazinone scaffold.

Potential Commercial Applications: Competitive Advantages:
  • Targeted therapeutic agent for cancer and other cell proliferation disorders.
 
  • Compounds are specific to one isoform of pyruvate kinase
  • Compounds target tumor cells and not normal cells, so side effects may be reduced
  • Compounds are small molecules which may be further optimized


Development Stage:
  • Early-stage
  • In vitro data available


Related Invention(s):
E-326-2008-0
E-120-2010-0


Inventors:

Craig Thomas (NCATS)  ➽ more inventions...

Douglas Auld (NCATS)  ➽ more inventions...

Jian-kang Jiang (NCATS)  ➽ more inventions...

Matthew Boxer (NCATS)  ➽ more inventions...

Min Shen (NCATS)  ➽ more inventions...


Intellectual Property:
US Application No. 61/752,698

Publications:
Anastasiou D, et al. PMID 22922757
Anastasiou D, et al. PMID 22052977
Jiang J, et al. PMID 20451379

Collaboration Opportunity:

The National Center for Advancing Translational Sciences (NCATS) is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate or commercialize Pyruvate Kinase M2 Activators for the Treatment of Cancer. For collaboration opportunities, please contact the Office of Strategic Alliances at NCATSPartnerships@mail.nih.gov.


Licensing Contact:
Suryanarayana Vepa, Ph.D.
Email: sury.vepa@nih.gov
Phone: 301-217-9197

OTT Reference No: E-298-2011-1
Updated: May 7, 2018