A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2
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Date
2021-11-02T00:00:00
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Publisher
American Chemical Society
Abstract
The allosteric regulation of pyruvate kinase M2 (PKM2) affects the switching of the PKM2 protein between the high-activity and low-activity states that allow ATP and lactate production, respectively. PKM2, in its low catalytic state (dimeric form), is chiefly active in metabolically energetic cells, including cancer cells. More recently, PKM2 has emerged as an attractive target due to its role in metabolic dysfunction and other interrelated conditions. PKM2 (dimer) activity can be inhibited by modulating PKM2 dimer�tetramer dynamics using either PKM2 inhibitors that bind at the ATP binding active site of PKM2 (dimer) or PKM2 activators that bind at the allosteric site of PKM2, thus activating PKM2 from the dimer formation to the tetrameric formation. The present perspective focuses on medicinal chemistry approaches to design and discover PKM2 inhibitors and activators and further provides a scope for the future design of compounds targeting PKM2 with better efficacy and selectivity. � 2021 American Chemical Society
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Keywords
Allosteric Regulation, Allosteric Site, Carrier Proteins, Chemistry, Pharmaceutical, Glycolysis, Humans, Membrane Proteins, Protein Kinase Inhibitors, Thyroid Hormones, adenosine triphosphate, dimer, flavonoid, phenol derivative, phytochemical, pyruvate kinase, pyruvate kinase M2, tetramer, unclassified drug, carrier protein, membrane protein, protein kinase inhibitor, thyroid hormone, thyroid hormone-binding proteins, allosteric site, allosterism, antineoplastic activity, cancer chemotherapy, dimerization, drug binding site, drug design, drug efficacy, drug selectivity, drug targeting, enzyme mechanism, human, medicinal chemistry, nonhuman, Review, structure activity relation, tetramerization, glycolysis