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.
Click here for help

Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

✖

View interactive charts of activity data across species
2D Structure
Click here for help

2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

✖
Click here for structure editor
Physico-chemical Properties
Click here for help

Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

✖
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
SMILES / InChI / InChIKey
Click here for help

SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

✖
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
InChI Key XAYGBKHKBBXDAK-UHFFFAOYSA-N
No information available.
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 ClinicalTrials.gov'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