compound 20 [PMID: 30998356]   Click here for help

GtoPdb Ligand ID: 10371

PDB Ligand
Compound class: Synthetic organic
Comment: Compound 20 was rationally designed as a potent, selective and orally active TTK protein kinase inhibitor with single agent efficacy against triple negative breast cancer cells [1]. The pyrrolopyrimidine core of 20 interacts with residues within TTK's ATP binding pocket, and it forms three hydrogen bonds to the hinge region. The ligand/TTK co-crystal structure has been submitted to the PDB and has ID 6N6O.
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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 3
Rotatable bonds 9
Topological polar surface area 112.6
Molecular weight 555.19
XLogP 6.12
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 CN(C(=O)c1ccc(c(c1)OC(C(F)(F)F)C)Nc1nc(OC2CCC(CC2)(C)O)c2c(n1)[nH]cc2Cl)C
Isomeric SMILES CN(C(=O)c1ccc(c(c1)O[C@@H](C(F)(F)F)C)Nc1nc(O[C@@H]2CC[C@](CC2)(C)O)c2c(n1)[nH]cc2Cl)C
InChI InChI=1S/C25H29ClF3N5O4/c1-13(25(27,28)29)37-18-11-14(22(35)34(3)4)5-6-17(18)31-23-32-20-19(16(26)12-30-20)21(33-23)38-15-7-9-24(2,36)10-8-15/h5-6,11-13,15,36H,7-10H2,1-4H3,(H2,30,31,32,33)/t13-,15-,24+/m1/s1
InChI Key IUWWRSQCDUQDEZ-CAQPCFEESA-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 20 potently inhibits TTK autophosphorylation (IC50 11 nM) and phosphorylation of the direct TTK substrate KNL1 (IC50 30 nM) [1]. It inhibits proliferation of CAL-51 triple negative breast cancer cells with an IC50 of 10 nM in vitro. Potential off targets include LRRK2G2019S, LRRK2 (wild type), JNK1, JNK2, DYRK3, JNK3, TSSK1, CLK2 and Ltk which were all inhibited by >80% in the presence of 3 μM compound 20 in a kinase screening evaluation. Only LRRK2G2019S, LRRK2, JNK1 and JNK2 had IC50 values within 100-fold of TTK.
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
TTK protein kinase Primary target of this compound Hs Inhibitor Inhibition 9.1 pIC50 - 1
⤷ pIC50 9.1 (IC50 7x10-10 M) [1]
Description: In vitro inhibitory activity using the proprietary LanthaScreen Eu kinase binding assay.
leucine rich repeat kinase 2 Hs Inhibitor Inhibition 9.0 pIC50 - 1
⤷ pIC50 9.0 (IC50 1x10-9 M) [1]
Description: Measuring in vitro enzyme inhibitory activity.
mitogen-activated protein kinase 8 Hs Inhibitor Inhibition 7.5 pIC50 - 1
⤷ pIC50 7.5 (IC50 3.2x10-8 M) [1]
Description: Measuring in vitro enzyme inhibitory activity.
mitogen-activated protein kinase 9 Hs Inhibitor Inhibition 7.2 pIC50 - 1
⤷ pIC50 7.2 (IC50 5.9x10-8 M) [1]
Description: Measuring in vitro enzyme inhibitory activity.
dual specificity tyrosine phosphorylation regulated kinase 3 Hs Inhibitor Inhibition 7.0 pIC50 - 1
⤷ pIC50 7.0 (IC50 1.04x10-7 M) [1]
Description: Measuring in vitro enzyme inhibitory activity.
mitogen-activated protein kinase 10 Hs Inhibitor Inhibition 7.0 pIC50 - 1
⤷ pIC50 7.0 (IC50 1.07x10-7 M) [1]
Description: Measuring in vitro enzyme inhibitory activity.
testis specific serine kinase 1B Hs Inhibitor Inhibition 6.7 pIC50 - 1
⤷ pIC50 6.7 (IC50 2.17x10-7 M) [1]
Description: Measuring in vitro enzyme inhibitory activity.
CDC like kinase 2 Hs Inhibitor Inhibition 6.6 pIC50 - 1
⤷ pIC50 6.6 (IC50 2.61x10-7 M) [1]
Description: Measuring in vitro enzyme inhibitory activity.
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
leukocyte receptor tyrosine kinase Hs Inhibitor Inhibition 6.3 pKi - 1
⤷ pKi 6.3 (Ki 5.67x10-7 M) [1]
Description: Measuring in vitro enzyme inhibitory activity.