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
Click here for help
Click here for structure editor
Physico-chemical Properties
Click here for help
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
Click here for help
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)
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