compound 8i [PMID: 22765894]   Click here for help

GtoPdb Ligand ID: 9905

Compound class: Synthetic organic
Comment: Compound 8i is a multi-target receptor tyrosine kinase inhibitor [1]. The chemical structure matches that ascribed to the Exelixis compound XL999 presented by MedKoo, but there is no peer reviewed confirmation of this nomenclature linkage.
Compound 8i does not alter c-MET activity, so its effects can be compared to those of foretinib and/or cabozantinib which are c-MET inhibitors, to help assess the contribition that inhibition of the different kinases makes to measured outcomes (e.g. antiproliferative effect).
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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 5
Hydrogen bond donors 3
Rotatable bonds 5
Topological polar surface area 73.05
Molecular weight 445.23
XLogP 3.77
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 CCN1CCC(CC1)Nc1ccc2c(c1)C(=C(c1ncc([nH]1)C)c1cccc(c1)F)C(=O)N2
Isomeric SMILES CCN1CCC(CC1)Nc1ccc2c(c1)/C(=C(/c1ncc([nH]1)C)\c1cccc(c1)F)/C(=O)N2
InChI InChI=1S/C26H28FN5O/c1-3-32-11-9-19(10-12-32)30-20-7-8-22-21(14-20)24(26(33)31-22)23(25-28-15-16(2)29-25)17-5-4-6-18(27)13-17/h4-8,13-15,19,30H,3,9-12H2,1-2H3,(H,28,29)(H,31,33)/b24-23-
InChI Key DMQYDVBIPXAAJA-VHXPQNKSSA-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 8i is potent inhibitor of key receptor tyrosine kinases (e.g. FGFR, VEGFRs and PDGFRs) that are implicated in the development and maintenance of tumour vasculature, and in the proliferation of some tumour cell types. Potent inhibition of FLT3 by compound 8i may be effective in down-modulating leukemia cell proliferation in AML.
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
fms related receptor tyrosine kinase 3 Hs Inhibitor Inhibition 9.1 pIC50 - 2
⤷ pIC50 9.1 (IC50 8x10-10 M) [2]
platelet derived growth factor receptor beta Hs Inhibitor Inhibition 8.8 pIC50 - 2
⤷ pIC50 8.8 (IC50 1.5x10-9 M) [2]
platelet derived growth factor receptor alpha Hs Inhibitor Inhibition 8.7 pIC50 - 1
⤷ pIC50 8.7 (IC50 2x10-9 M) [1]
fms related receptor tyrosine kinase 4 Hs Inhibitor Inhibition 8.5 pIC50 - 2
⤷ pIC50 8.5 (IC50 3x10-9 M) [2]
kinase insert domain receptor Hs Inhibitor Inhibition 8.4 – 8.6 pIC50 - 1-2
⤷ pIC50 8.6 (IC50 2.6x10-9 M) [2]
pIC50 8.4 (IC50 4x10-9 M) [1]
AXL receptor tyrosine kinase Hs Inhibitor Inhibition 8.3 pIC50 - 2
⤷ pIC50 8.3 (IC50 4.6x10-9 M) [2]
fibroblast growth factor receptor 1 Hs Inhibitor Inhibition 8.2 – 8.4 pIC50 - 1-2
⤷ pIC50 8.4 (IC50 4x10-9 M) [1]
pIC50 8.2 (IC50 6.2x10-9 M) [2]
KIT proto-oncogene, receptor tyrosine kinase Hs Inhibitor Inhibition 7.9 pIC50 - 2
⤷ pIC50 7.9 (IC50 1.38x10-8 M) [2]
fms related receptor tyrosine kinase 1 Hs Inhibitor Inhibition 7.5 – 7.7 pIC50 - 1-2
⤷ pIC50 7.7 (IC50 2x10-8 M) [1]
pIC50 7.5 (IC50 2.9x10-8 M) [2]
macrophage stimulating 1 receptor Hs Inhibitor Inhibition 6.9 pIC50 - 2
⤷ pIC50 6.9 (IC50 1.24x10-7 M) [2]
TEK receptor tyrosine kinase Hs Inhibitor Inhibition 6.6 pIC50 - 2
⤷ pIC50 6.6 (IC50 2.7x10-7 M) [2]
MET proto-oncogene, receptor tyrosine kinase Hs Inhibitor Inhibition 6.3 pIC50 - 2
⤷ pIC50 6.3 (IC50 4.63x10-7 M) [2]