CHMFL-KIT-64   Click here for help

GtoPdb Ligand ID: 10420

Synonyms: compound 18 [PMID: 31250638]
Compound class: Synthetic organic
Comment: CHMFL-KIT-64 is a potent and orally available inhibitor of wild-type c-KIT and a range of known c-KIT resistance mutants [1]. It has demonstrated anti-tumour efficacy in vitro, in mouse xenograft models, and against imatinib-resistant patient tumour cells expressing wild-type c-KIT. It has been proposed as a potential clinical lead for gastrointestinal stromal tumour (GIST) therapy as the majority (80-85%) of GISTs harbour c-KIT activation mutations. Other c-KIT mutations confer primary or secondary (acquired) resistance to imatinib which is the first line drug used to combat GISTs. CHMFL-KIT-64 was designed to target mutations that are refractory to currently approved therapeutics including imatinib, sunitinib and regorafenib. It can potently inhibit the T670I ATP binding pocket (gatekeeper) mutant that is resistant to many other c-KIT inhibitors.
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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 3
Hydrogen bond donors 1
Rotatable bonds 9
Topological polar surface area 69.68
Molecular weight 516.11
XLogP 5.5
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 COc1cc2nccc(c2cc1OC)Oc1ccc(cc1)NC(=O)Cc1ccc(c(c1)C(F)(F)F)Cl
Isomeric SMILES COc1cc2nccc(c2cc1OC)Oc1ccc(cc1)NC(=O)Cc1ccc(c(c1)C(F)(F)F)Cl
InChI InChI=1S/C26H20ClF3N2O4/c1-34-23-13-18-21(14-24(23)35-2)31-10-9-22(18)36-17-6-4-16(5-7-17)32-25(33)12-15-3-8-20(27)19(11-15)26(28,29)30/h3-11,13-14H,12H2,1-2H3,(H,32,33)
InChI Key YOHLRCOPRAVUCJ-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
CHMFL-KIT-64 exhibits favourable potencies against the majority of the gain-of-function mutations in the juxtamembrane domain, drug-resistant mutations in the ATP binding pocket (but not V654A), and activation loops (except D816V).
CHMFL-KIT-64 inhibits proliferation of BaF3 cells expressing the c-KIT T670I mutant by 90%, and inhibits enzyme activity with an IC50 of 8 nM in a biochemical assay [1]. Kinome screening reveals that c-KIT, PDGFRα, PDGFRβ, and CSF1R kinases are the main targets of CHMFL-KIT-64. These are all type III receptor tyrosine kinase family members whose ATP binding pockets are highly conserved.
Selectivity at catalytic receptors
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
KIT proto-oncogene, receptor tyrosine kinase Hs Inhibitor Inhibition 8.4 pIC50 - 1
⤷ pIC50 8.4 (IC50 4x10-9 M) [1]
Description: In a biochemical assay.
colony stimulating factor 1 receptor Hs Inhibitor Inhibition 7.7 pIC50 - 1
⤷ pIC50 7.7 (IC50 1.8x10-8 M) [1]
Description: In a biochemical assay.
platelet derived growth factor receptor alpha Hs Inhibitor Inhibition 7.6 pIC50 - 1
⤷ pIC50 7.6 (IC50 2.5x10-8 M) [1]
Description: In a biochemical assay.
platelet derived growth factor receptor beta Hs Inhibitor Inhibition 7.0 pIC50 - 1
⤷ pIC50 7.0 (IC50 9.7x10-8 M) [1]
Description: In a biochemical assay.
fms related receptor tyrosine kinase 4 Hs Inhibitor Inhibition 6.9 pIC50 - 1
⤷ pIC50 6.9 (IC50 1.21x10-7 M) [1]
Description: In a biochemical assay.
discoidin domain receptor tyrosine kinase 1 Hs Inhibitor Inhibition 6.9 pIC50 - 1
⤷ pIC50 6.9 (IC50 1.35x10-7 M) [1]
Description: In a biochemical assay.