compound 52 [PMID: 36749735]   Click here for help

GtoPdb Ligand ID: 12412

Compound class: Synthetic organic
Comment: This compound is an inhibitor of EGFR with double mutations at L858R (activating mutation) and T790M (gatekeeper resistance mutation) [1]. It was designed to combat advanced tumours that are driven by this mutated kinase, whilst sparing function of the wild type EGFR.
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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.

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View interactive charts of activity data across species
2D Structure
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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.

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Physico-chemical Properties
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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.

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Hydrogen bond acceptors 8
Hydrogen bond donors 2
Rotatable bonds 11
Topological polar surface area 81.56
Molecular weight 498.62
XLogP 2.53
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
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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/)

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Canonical SMILES C=CC(=O)NC1=C(C=CC(=C1)C2=C(C3=CC=CC=C3)OC4=C2C(=NC=N4)NC(C)C)N(C)CCN(C)C
Isomeric SMILES CN(CCN(C)C)C=1C(NC(C=C)=O)=CC(=CC1)C2=C(C3=CC=CC=C3)OC4=C2C(NC(C)C)=NC=N4
InChI InChI=1S/C29H34N6O2/c1-7-24(36)33-22-17-21(13-14-23(22)35(6)16-15-34(4)5)25-26-28(32-19(2)3)30-18-31-29(26)37-27(25)20-11-9-8-10-12-20/h7-14,17-19H,1,15-16H2,2-6H3,(H,33,36)(H,30,31,32)
InChI Key YGHKTUWZPBGQHE-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/)
Bioactivity Comments
Although the selectivity of compound 52 for EGFRL858R/T790M compared to WT EGFR is low in an enzymatic activity assay (1.7-fold), its selectivity is increased in model cells lines [1]. Compound 52 produces an antitumour effect in xenograft models of EGFRL858R/T790M-driven cancer.
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
epidermal growth factor receptor Hs Inhibitor Inhibition 7.6 – 7.8 pIC50 - 1
⤷ pIC50 7.8 (IC50 1.5x10-8 M) [1]
Description: Inhibition of EGFRL858R/T790M enzyme activity
pIC50 7.6 (IC50 2.5x10-8 M) [1]
Description: Inhibition of WT EGFR enzymatic activity