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.