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Updated: Jun 17, 2026
Identification of Novel CK2 Kinase Substrates Using a Versatile Biochemical Approach
Published on: February 21, 2019
Identification of small molecule inhibitors of pyruvate kinase M2
Matthew G Vander Heiden1, Heather R Christofk, Eli Schuman
1Dana-Farber Cancer Institute, Boston, MA 02115, United States.
Abstract:
A common feature of tumors arising from diverse tissue types is a reliance on aerobic glycolysis for glucose metabolism. This metabolic difference between cancer cells and normal cells could be exploited for therapeutic benefit in patients. Cancer cells universally express the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), and previous work has demonstrated that PKM2 expression is necessary for aerobic glycolysis and cell proliferation in vivo. Because most normal tissues express an isoform of pyruvate kinase other than PKM2, selective targeting of PKM2 provides an opportunity to target cell metabolism for cancer therapy. PKM2 has an identical catalytic site as the related M1 splice variant (PKM1). However, isoform selective inhibition is possible as PKM2 contains a unique region for allosteric regulation. We have screened a library of greater than 1,00,000 small molecules to identify such inhibitors. The inhibitors identified for PKM2 fell primarily into three distinct structural classes. The most potent PKM2 inhibitor resulted in decreased glycolysis and increased cell death following loss of growth factor signaling. At least part of this effect was due to on-target PKM2 inhibition as less cell death was observed in cells engineered to express PKM1. These data suggest that isoform selective inhibition of PKM2 with small molecules is feasible and support the hypothesis that inhibition of glucose metabolism in cancer cells is a viable strategy to treat human malignancy.
Insights
Researchers identified small molecules that selectively inhibit pyruvate kinase M2 (PKM2), an enzyme crucial for cancer cell metabolism. This targeted inhibition offers a promising strategy for cancer therapy by disrupting tumor growth and promoting cell death.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Tumors commonly utilize aerobic glycolysis for energy.
- Pyruvate kinase M2 (PKM2) is essential for cancer cell proliferation and aerobic glycolysis.
- PKM2's unique allosteric site allows for isoform-selective targeting, differentiating it from PKM1.
Purpose of the Study:
- To identify small molecule inhibitors selective for PKM2.
- To investigate the therapeutic potential of targeting PKM2 in cancer.
Main Methods:
- Screening of over 100,000 small molecules to find PKM2 inhibitors.
- Assessing the impact of PKM2 inhibition on glycolysis and cell death.
- Comparing effects in cells expressing PKM2 versus PKM1.
Main Results:
- Identified potent PKM2 inhibitors belonging to three distinct structural classes.
- PKM2 inhibition decreased glycolysis and increased cancer cell death, especially after growth factor withdrawal.
- On-target inhibition was confirmed by reduced cell death in PKM1-expressing cells.
Conclusions:
- Selective inhibition of PKM2 with small molecules is feasible.
- Targeting cancer cell glucose metabolism via PKM2 inhibition is a viable therapeutic strategy.
