compound 19a [PMID: 30503936]   Click here for help

GtoPdb Ligand ID: 10181

Compound class: Synthetic organic
Comment: Compound 19a was designed as a small molecule type II kinase inhibitor to target c-Met in cancers, with improved drug-like properties, and pharmacokinetic and toxicity profiles compared to previously reported inhibitors of c-Met [1]. It is a multi-tyrosine kinase inhibitor with targets including c-Met, Ron (macrophage stimulating 1 receptor), c-Kit, AXL and IGF-1R, and it is reported to be effective against drug-sensitive and drug-resistant cancer cell lines.
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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 14
Topological polar surface area 133.8
Molecular weight 728.24
XLogP 4.87
No. Lipinski's rules broken 1

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 CCN1CCN(CC1)CCCOc1cc2nccc(c2cc1OC)Oc1c(F)cc(cc1F)NC(=O)NN1C(=O)CSC1c1c(F)cccc1F
Isomeric SMILES CCN1CCN(CC1)CCCOc1cc2nccc(c2cc1OC)Oc1c(F)cc(cc1F)NC(=O)NN1C(=O)CSC1c1c(F)cccc1F
InChI InChI=1S/C35H36F4N6O5S/c1-3-43-11-13-44(14-12-43)10-5-15-49-30-19-27-22(18-29(30)48-2)28(8-9-40-27)50-33-25(38)16-21(17-26(33)39)41-35(47)42-45-31(46)20-51-34(45)32-23(36)6-4-7-24(32)37/h4,6-9,16-19,34H,3,5,10-15,20H2,1-2H3,(H2,41,42,47)
InChI Key GZVQZLVAKXRTHU-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
Compound 19a exhibits cytotoxicity and anti-proliferative activity against HT-29 cancer cells, with an in vitro efficacy greater than cabozantinib (an approved multi-kinase inhibitor with potent activity against c-Met) [1]. The in vitro IC50 for inhibition of HT-29 cell proliferation is 73 nM, for A549 cells it is 350 nM, for cisplatin-resistant A549DDP cells it is 630 nM, and for MDA-MB-231 cells it is 3100 nM [1].
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
SRC proto-oncogene, non-receptor tyrosine kinase Hs Inhibitor Inhibition 6.6 pIC50 - 1
⤷ pIC50 6.6 (IC50 2.4x10-7 M) [1]
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
macrophage stimulating 1 receptor Hs Inhibitor Inhibition 8.5 pIC50 - 1
⤷ pIC50 8.5 (IC50 2.9x10-9 M) [1]
MET proto-oncogene, receptor tyrosine kinase Hs Inhibitor Inhibition 7.8 pIC50 - 1
⤷ pIC50 7.8 (IC50 1.5x10-8 M) [1]
AXL receptor tyrosine kinase Hs Inhibitor Inhibition 7.3 pIC50 - 1
⤷ pIC50 7.3 (IC50 5.3x10-8 M) [1]
KIT proto-oncogene, receptor tyrosine kinase Hs Inhibitor Inhibition 7.2 pIC50 - 1
⤷ pIC50 7.2 (IC50 6.4x10-8 M) [1]
epidermal growth factor receptor Hs Inhibitor Inhibition 6.3 pIC50 - 1
⤷ pIC50 6.3 (IC50 5.2x10-7 M) [1]
kinase insert domain receptor Hs Inhibitor Inhibition 6.1 pIC50 - 1
⤷ pIC50 6.1 (IC50 8.5x10-7 M) [1]
Insulin-like growth factor I receptor Hs Inhibitor Inhibition 5.7 pIC50 - 1
⤷ pIC50 5.7 (IC50 2.1x10-6 M) [1]