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
1. Al-Samkari H, Galactéros F, Glenthøj A, Rothman JA, Andres O, Grace RF, Morado-Arias M, Layton DM, Onodera K, Verhovsek M et al.. (2022)
Mitapivat versus Placebo for Pyruvate Kinase Deficiency.
N Engl J Med, 386 (15): 1432-1442. [PMID:35417638]
2. Canu G, De Bonis M, Minucci A, Capoluongo E. (2016)
Red blood cell PK deficiency: An update of PK-LR gene mutation database.
Blood Cells Mol Dis, 57: 100-9. [PMID:26832193]
3. EMA. 
EU/3/20/2270; mitapivat orphan designation.
Accessed on 23/02/2022. Modified on 23/02/2022.,
4. Grace RF, Rose C, Layton DM, Galactéros F, Barcellini W, Morton DH, van Beers EJ, Yaish H, Ravindranath Y, Kuo KHM et al.. (2019)
Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency.
N Engl J Med, 381 (10): 933-944. [PMID:31483964]
5. Kung C, Hixon J, Kosinski PA, Cianchetta G, Histen G, Chen Y, Hill C, Gross S, Si Y, Johnson K et al.. (2017)
AG-348 enhances pyruvate kinase activity in red blood cells from patients with pyruvate kinase deficiency.
Blood, 130 (11): 1347-1356. [PMID:28760888]
6. Rab MAE, Van Oirschot BA, Kosinski PA, Hixon J, Johnson K, Chubukov V, Dang L, Pasterkamp G, Van Straaten S, Van Solinge WW et al.. (2021)
AG-348 (Mitapivat), an allosteric activator of red blood cell pyruvate kinase, increases enzymatic activity, protein stability, and ATP levels over a broad range of PKLR genotypes.
Haematologica, 106 (1): 238-249. [PMID:31974203]
7. Saunders JO, Salituro FG, Yan S. (2011)
Therapeutic compounds and compositions.
Patent number: WO2011002817A1. Assignee: Agios Pharmaceuticals, Inc.. Priority date: 29/06/2009. Publication date: 06/01/2011.