EAI045   Click here for help

GtoPdb Ligand ID: 9222

Compound class: Synthetic organic
Comment: EAI045 is an allosteric inhibitor of mutant forms of the EGFR found in lung cancers whilst sparing the wild-type receptor [1]. Allosteric inhibitors are being developed to overcome acquired resistance to current EGFR tyrosine kinase inhibitors which bind to the ATP pocket of the enzyme, which is the location of the many identified resistance mutations.
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 CDK toolkit. 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 2
Rotatable bonds 5
Topological polar surface area 110.77
Molecular weight 383.07
XLogP 1.9
No. Lipinski's rules broken 0
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.

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Canonical SMILES Fc1ccc(c(c1)C(N1Cc2c(C1=O)cccc2)C(=O)Nc1nccs1)O
Isomeric SMILES Fc1ccc(c(c1)C(N1Cc2c(C1=O)cccc2)C(=O)Nc1nccs1)O
InChI InChI=1S/C19H14FN3O3S/c20-12-5-6-15(24)14(9-12)16(17(25)22-19-21-7-8-27-19)23-10-11-3-1-2-4-13(11)18(23)26/h1-9,16,24H,10H2,(H,21,22,25)
InChI Key YTUFHOKUFOQRDF-UHFFFAOYSA-N
Bioactivity Comments
EAI045 inhibits L858R/T790M mutant EGFR with an IC50 of 3nM and is >1000-fold selective for this mutant compared to wild-type receptor [1]. In screening panels EAI045 did not inhibit any other kinases by >20% (at 1000nM EAI045), or show any liability against non-kinase targets. In animal models EAI045 is most effective in combination with cetuximab, a monoclonal antibody which effectively blocks ligand-induced EGFR dimerization and enhances the population of receptor subunits susceptible to the allosteric inhibitor [1]. In xenograft models EAI045 is effective against EGFR(L858R/T790M/C797S) tumours, a mutation profile that is resistant to all currently available ATP-competitive EGFR tyrosine kinase inhibitors.
We have included EAI045 in the interactions table below, for data retrieval purposes, but note that this compound DOES NOT significantly inhibit wild-type EGFR tyrosine kinase 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
epidermal growth factor receptor Hs Allosteric modulator Inhibition - - - 1
⤷ [1]