lumacaftor   Click here for help

GtoPdb Ligand ID: 7481

Synonyms: VRT-826809 | VX-809 | VX809
Approved drug PDB Ligand
lumacaftor is an approved drug (EMA & FDA (2015))
Compound class: Synthetic organic
Comment: Lumacaftor is termed a cystic fibrosis transmembrane conductance regulator (CFTR) corrector, acting to reduce mis-folding of the defective F508del mutant CFTR protein, in comparison to ivacaftor which is termed a CFTR potentiator drug. The F508del mutation is the most common cause of cystic fibrosis and accounts for approximately 60% of CF patients in Europe. Cryo-electron microscopy of CFTR-lumacaftor complexes provided insight into how the correctors operate at the molecular level, with the findings published in early 2022 by Fiedorczuk and Chen [1].
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

IUPHAR Pharmacology Education Project (PEP) logo

View more information in the IUPHAR Pharmacology Education Project: lumacaftor

lumacaftor is commercially available from our sponsors

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 Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). 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 5
Hydrogen bond donors 2
Rotatable bonds 6
Topological polar surface area 97.75
Molecular weight 452.12
XLogP 4.93
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
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.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

✖
Canonical SMILES O=C(C1(CC1)c1ccc2c(c1)OC(O2)(F)F)Nc1ccc(c(n1)c1cccc(c1)C(=O)O)C
Isomeric SMILES O=C(C1(CC1)c1ccc2c(c1)OC(O2)(F)F)Nc1ccc(c(n1)c1cccc(c1)C(=O)O)C
InChI InChI=1S/C24H18F2N2O5/c1-13-5-8-19(27-20(13)14-3-2-4-15(11-14)21(29)30)28-22(31)23(9-10-23)16-6-7-17-18(12-16)33-24(25,26)32-17/h2-8,11-12H,9-10H2,1H3,(H,29,30)(H,27,28,31)
InChI Key UFSKUSARDNFIRC-UHFFFAOYSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
No information available.
Summary of Clinical Use Click here for help
In 2015, a fixed-dose combination of lumacaftor plus ivacaftor (Orkambi®) was approved (EMA & FDA) for the treatment of cystic fibrosis patients aged 12 years and older carrying the F508del mutation. FDA approval for Orkambi® was expanded in October 2016 to include children with cystic fibrosis aged 6 to 11 who are homozygous for the F508del mutation.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
VX-809 is reported to correct protein mis-folding in one of the two transmembrane domains of the F508del-CFTR [4]. This effects partial restoration of functional CFTR channels. Combination therapy with compounds with different structure-guided mechanisms by which they correct CFTR function (e.g. Ivacaftor) may provide additional benefit in the treatment of CF [2].