Abstract
Pyruvate kinase (PK) deficiency is a rare genetic disease that causes chronic hemolytic anemia. There are currently no targeted therapies for PK deficiency. Here, we describe the identification and characterization of AG-348, an allosteric activator of PK that is currently in clinical trials for the treatment of PK deficiency. We demonstrate that AG-348 can increase the activity of wild-type and mutant PK enzymes in biochemical assays and in patient red blood cells treated ex vivo. These data illustrate the potential for AG-348 to restore the glycolytic pathway activity in patients with PK deficiency and ultimately lead to clinical benefit.
© 2017 by The American Society of Hematology.
MeSH terms
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Anemia, Hemolytic, Congenital Nonspherocytic
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Animals
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Enzyme Activation / drug effects
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Enzyme Activators / chemistry
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Enzyme Activators / pharmacology*
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Enzyme Activators / therapeutic use*
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Erythrocytes / drug effects
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Erythrocytes / enzymology*
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Humans
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Kinetics
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Mice
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Piperazines
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Pyruvate Kinase / deficiency*
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Pyruvate Kinase / drug effects
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Pyruvate Kinase / metabolism*
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Pyruvate Metabolism, Inborn Errors
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Quinolines / chemistry
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Quinolines / pharmacology*
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Quinolines / therapeutic use*
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Recombinant Proteins / metabolism
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
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Sulfonamides / therapeutic use*
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Tissue Donors
Substances
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Enzyme Activators
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Piperazines
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Quinolines
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Recombinant Proteins
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Sulfonamides
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mitapivat
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Pyruvate Kinase
Supplementary concepts
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Pyruvate Kinase Deficiency of Red Cells