mitapivat   Click here for help

GtoPdb Ligand ID: 10473

Synonyms: AG-348 | AG348 | compound 80a [WO2011002817A1] | PKM2 activator 1020 | PKR-IN-1 | Pyrukynd®
Approved drug
mitapivat is an approved drug (EMA & FDA (2022))
Compound class: Synthetic organic
Comment: Mitapivat (AG-348) is a first-in-class, small molecule allosteric activator of the pyruvate kinases. It activates the PK isoform that is found in erythrocytes (PKR protein that is expressed from the PKLR gene) and the embryonic PKM2 isoform (expressed from the PKM gene) that is only expressed by cancer cells in adult tissues. Mitapivat was developed by Agios Pharmaceuticals as a novel therapy for diseases of red blood cells that are associated with inherited PKR deficiency [2], and for potential in cancer therapy via activation of PKM2. Activation of PK in red cells increases hemoglobin levels [4-5]. The active drug is the sulfate hydrate (PubChem CID 134693700). We show the structure for the parent molecule as described by its INN.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 7
Hydrogen bond donors 1
Rotatable bonds 7
Topological polar surface area 90.99
Molecular weight 450.17
XLogP 2.75
No. Lipinski's rules broken 0
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Canonical SMILES O=C(c1ccc(cc1)NS(=O)(=O)c1cccc2c1nccc2)N1CCN(CC1)CC1CC1
Isomeric SMILES O=C(c1ccc(cc1)NS(=O)(=O)c1cccc2c1nccc2)N1CCN(CC1)CC1CC1
InChI InChI=1S/C24H26N4O3S/c29-24(28-15-13-27(14-16-28)17-18-6-7-18)20-8-10-21(11-9-20)26-32(30,31)22-5-1-3-19-4-2-12-25-23(19)22/h1-5,8-12,18,26H,6-7,13-17H2
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Summary of Clinical Use Click here for help
Pyruvate kinase deficiency is caused by mutations in the PKLR gene and leads to congenital hemolytic anemia [6]. AG-348 was progressed to Phase 3 clinical evaluation in patients with pyruvate kinase deficiency, and results were published in April 2022 [1]. Trials in patients with sickle cell disease are also underway. Click here to link to's full list of AG-348 studies.
The EMA issued orphan designation in April 2020, which permitted mitapivat to be used to treat pyruvate kinase deficiency [3], The FDA granted full approval in February 2022, which indicated mitapivat as a therapeutic for the treatment of adults with hemolytic anemia that is caused by PK deficiency.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02476916 A Study of AG-348 in Adult Participants With Pyruvate Kinase (PK) Deficiency Phase 2 Interventional Agios Pharmaceuticals, Inc. 4
NCT03559699 A Study Evaluating the Efficacy and Safety of AG-348 in Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD) Phase 3 Interventional Agios Pharmaceuticals, Inc. 4
NCT04610866 Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Long-term Mitapivat Dosing in Subjects With Stable Sickle Cell Disease: An Extension of a Phase I Pilot Study of Mitapivat Phase 1/Phase 2 Interventional National Institutes of Health Clinical Center (CC) 4
NCT03548220 A Study to Evaluate Efficacy and Safety of AG-348 in Not Regularly Transfused Adult Participants With Pyruvate Kinase Deficiency (PKD) Phase 3 Interventional Agios Pharmaceuticals, Inc. In this study, mitapivat (24 weeks of treatment) significantly increased haemoglobin, decreased hemolysis and improved self-reported outcomes (in patients with pyruvate kinase deficiency) compared to placebo controls [1]. 1,4