DDR1/2 inhibitor 5n   Click here for help

GtoPdb Ligand ID: 10105

PDB Ligand Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: The DDR1 and DDR2 receptor tyrosine kinases are new potential targets for anti-inflammatory drug discovery, as they are critical mediators of inflammatory cytokine secretion whose dysregulation is implicated in the progression of various human inflammatory diseases, including fibrosis, arthritis, atherosclerosis and cancer [1-2]. The dual inhibitor compound 5n was designed to investigate the anti-inflammatory potential of coinhibiting these enzymes, and provides a lead scaffold for further optimisation [3].
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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 6
Hydrogen bond donors 1
Rotatable bonds 7
Topological polar surface area 65.77
Molecular weight 560.25
XLogP 5.74
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 CN1CCN(CC1)Cc1cc(NC(=O)c2ccc(c(c2)C#Cc2cnc3n2ccnc3)C(C)C)cc(c1)C(F)(F)F
Isomeric SMILES CN1CCN(CC1)Cc1cc(NC(=O)c2ccc(c(c2)C#Cc2cnc3n2ccnc3)C(C)C)cc(c1)C(F)(F)F
InChI InChI=1S/C31H31F3N6O/c1-21(2)28-7-5-24(16-23(28)4-6-27-18-36-29-19-35-8-9-40(27)29)30(41)37-26-15-22(14-25(17-26)31(32,33)34)20-39-12-10-38(3)11-13-39/h5,7-9,14-19,21H,10-13,20H2,1-3H3,(H,37,41)
InChI Key IUGBGEUCXVKGQK-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
Kd binding affinities for a number of off-targets are included in the tables below. These values were determined using DiscoveRx's kinase screening platform. In human primary lung fibroblasts inhibitor 5n dose-dependently inhibits the phosphorylation of DDR1 and DDR2, but has no effect of the phosphorylation status of ABL1 [3]. It reduces LPS-induced IL-6 release from mouse primary peritoneal macrophages in vitro, which supports its potential as an anti-inflammatory agent..
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
serine/threonine kinase 10 Hs Inhibitor Inhibition 8.0 pKd - 3
⤷ pKd 8.0 (Kd 1x10-8 M) [3]
LCK proto-oncogene, Src family tyrosine kinase Hs Inhibitor Inhibition 6.7 pKd - 3
⤷ pKd 6.7 (Kd 1.8x10-7 M) [3]
ABL proto-oncogene 1, non-receptor tyrosine kinase Hs Inhibitor Inhibition 6.3 pIC50 - 3
⤷ pIC50 6.3 (IC50 4.94x10-7 M) [3]
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
discoidin domain receptor tyrosine kinase 1 Primary target of this compound Hs Inhibitor Inhibition 8.1 pKd - 3
⤷ pKd 8.1 (Kd 7.9x10-9 M) [3]
discoidin domain receptor tyrosine kinase 2 Primary target of this compound Hs Inhibitor Inhibition 8.1 pKd - 3
⤷ pKd 8.1 (Kd 8x10-9 M) [3]
neurotrophic receptor tyrosine kinase 3 Hs Inhibitor Inhibition 8.0 pKd - 3
⤷ pKd 8.0 (Kd 9.3x10-9 M) [3]
neurotrophic receptor tyrosine kinase 2 Hs Inhibitor Inhibition 8.0 pKd - 3
⤷ pKd 8.0 (Kd 1.1x10-8 M) [3]
EPH receptor A8 Hs Inhibitor Inhibition 7.1 pKd - 3
⤷ pKd 7.1 (Kd 7.9x10-8 M) [3]
neurotrophic receptor tyrosine kinase 1 Hs Inhibitor Inhibition 7.0 pKd - 3
⤷ pKd 7.0 (Kd 1x10-7 M) [3]
EPH receptor A7 Hs Inhibitor Inhibition 6.7 pKd - 3
⤷ pKd 6.7 (Kd 2x10-7 M) [3]
EPH receptor A2 Hs Inhibitor Inhibition 6.6 pKd - 3
⤷ pKd 6.6 (Kd 2.6x10-7 M) [3]
EPH receptor B2 Hs Inhibitor Inhibition 6.6 pKd - 3
⤷ pKd 6.6 (Kd 2.6x10-7 M) [3]
TEK receptor tyrosine kinase Hs Inhibitor Inhibition 6.4 pKd - 3
⤷ pKd 6.4 (Kd 3.7x10-7 M) [3]
discoidin domain receptor tyrosine kinase 1 Primary target of this compound Hs Inhibitor Inhibition 8.0 pIC50 - 3
⤷ pIC50 8.0 (IC50 9.4x10-9 M) [3]
discoidin domain receptor tyrosine kinase 2 Hs Inhibitor Inhibition 7.7 pIC50 - 3
⤷ pIC50 7.7 (IC50 2.04x10-8 M) [3]