New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

A recent research in cancer research demonstrates that tumor-specific pyruvate kinase M2 (PKM2) plays an important role in chromosome segregation and mitosis progression of tumor cells. To improve the drug development of TCM compounds, we aim to identify potent TCM compounds as lead compounds of PKM2 regulators. PONDR-Fit protocol was utilized to predict the disordered disposition in the binding domain of PKM2 protein before virtual screening as the disordered structure in the protein may cause the side effect and downregulation of the possibility of ligand to bind with target protein. MD simulation was performed to validate the stability of interactions between PKM2 proteins and each ligand after virtual screening. The top TCM compounds, saussureamine C and precatorine, extracted fromLycium chinenseMill. andAbrus precatoriusL., respectively, have higher binding affinities with target protein in docking simulation than control. They have stable H-bonds with residues A:Lys311 and some other residues in both chains of PKM2 protein. Hence, we propose the TCM compounds, saussureamine C and precatorine, as potential candidates as lead compounds for further study in drug development process with the PKM2 protein against cancer.

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Pyruvate kinase M2-deficiency in T cells leads to exacerbation of ConA hepatitis and alterations of T cell polarization

10.1055/s-0039-3402269 ◽

2020 ◽

Author(s):

K Moll ◽

S Weidemann ◽

S Huber ◽

G Tiegs ◽

AK Horst

Keyword(s):

T Cells ◽

T Cell ◽

Pyruvate Kinase ◽

Cell Polarization ◽

Pyruvate Kinase M2 ◽

T Cell Polarization

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Faculty Opinions recommendation of Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13414963.15219057 ◽

2012 ◽

Author(s):

Carlos Telleria

Keyword(s):

Reactive Oxygen Species ◽

Pyruvate Kinase ◽

Reactive Oxygen ◽

Oxygen Species ◽

Antioxidant Responses ◽

Pyruvate Kinase M2

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Faculty Opinions recommendation of Serine is a natural ligand and allosteric activator of pyruvate kinase M2.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717963431.793465419 ◽

2012 ◽

Author(s):

Hening Lin

Keyword(s):

Pyruvate Kinase ◽

Pyruvate Kinase M2 ◽

Natural Ligand ◽

Allosteric Activator

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Faculty Opinions recommendation of Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727547054.793533062 ◽

2017 ◽

Author(s):

Carolyn Ecelbarger

Keyword(s):

Mitochondrial Dysfunction ◽

Pyruvate Kinase ◽

Pyruvate Kinase M2

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Faculty Opinions recommendation of Class IIa Histone Deacetylases Drive Toll-like Receptor-Inducible Glycolysis and Macrophage Inflammatory Responses via Pyruvate Kinase M2.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.737444066.793576383 ◽

2020 ◽

Author(s):

George Kasotakis ◽

Brent Stanfield

Keyword(s):

Pyruvate Kinase ◽

Histone Deacetylases ◽

Inflammatory Responses ◽

Toll Like Receptor ◽

Pyruvate Kinase M2

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Discovery of boronic acid-based potent activators of tumor pyruvate kinase M2 and development of gastroretentive nanoformulation for oral dosing

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2021.128062 ◽

2021 ◽

pp. 128062

Author(s):

Rajkumar Patle ◽

Shital Shinde ◽

Sagarkumar Patel ◽

Rahul Maheshwari ◽

Heena Jariyal ◽

...

Keyword(s):

Pyruvate Kinase ◽

Boronic Acid ◽

Oral Dosing ◽

Pyruvate Kinase M2

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Valproic acid Suppresses Breast Cancer Cell Growth Through Triggering Pyruvate Kinase M2 Isoform Mediated Warburg Effect

Cell Transplantation ◽

10.1177/09636897211027524 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110275

Author(s):

Zhen Li ◽

Lina Yang ◽

Shuai Zhang ◽

Jiaqi Song ◽

Huanran Sun ◽

...

Keyword(s):

Breast Cancer ◽

Valproic Acid ◽

Cancer Therapy ◽

Pyruvate Kinase ◽

Histone Deacetylases ◽

Warburg Effect ◽

Broad Class ◽

Pyruvate Kinase M2 ◽

Breast Cancer Cell Growth ◽

The Warburg Effect

Energy metabolism programming is a hallmark of cancer, and serves as a potent target of cancer therapy. Valproic acid (VPA), a broad Class I histone deacetylases (HDACs) inhibitor, has been used as a therapeutic agent for cancer. However, the detail mechanism about the potential role of VPA on the Warburg effect in breast cancer remains unclear. In this study, we highlight that VPA significantly attenuates the Warburg effect by decreasing the expression of pyruvate kinase M2 isoform (PKM2), leading to inhibited cell proliferation and reduced colony formation in breast cancer MCF-7 and MDA-MB-231 cells. Mechanistically, Warburg effect suppression triggered by VPA was mediated by inactivation of ERK1/2 phosphorylation through reduced HDAC1 expression, resulting in suppressing breast cancer growth. In summary, we uncover a novel mechanism of VPA in regulating the Warburg effect which is essential for developing the effective approach in breast cancer therapy.

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