Activators for Human Pyruvate Kinase M2 as Leads in Cancer Therapeutics
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 potentially could 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, ML202 and ML170 represent 3 preclinical lead series that are highly specific allosteric activators of the tumor-specific isoform of human pyruvate kinase (M2 isoform). Both probes affect the cooperativity of phosphoenolpyruvate (PEP) binding, with little effect on adenosine diphosphate (ADP) binding, in a manner similar to FBP.
ML202 and ML203
National Center for Advancing Translational Sciences
Matthew B. Boxer, Ph.D.
Jian-kang Jiang, Ph.D.
Min Shen, Ph.D.
Craig J. Thomas, Ph.D.
Martin J. Walsh, Ph.D.
Koch Institute at Massachusetts Institute of Technology and the Dana-Farber Cancer Institute
Matthew G. Vander Heiden, Ph.D.
Beth Israel Deaconess Medical Center
Lewis C. Cantley, Ph.D.
Public Health Impact
The chemical probes developed in this project serve as starting points for drug development in cancer therapeutics. The compounds modulate cancer cell metabolism by the potent and specific activation of human human pyruvate kinase M2.
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