compound 52 [PMID: 36749735]   Click here for help

GtoPdb Ligand ID: 12412

Compound class: Synthetic organic
Comment: This compound is an inhibitor of EGFR with double mutations at L858R (activating mutation) and T790M (gatekeeper resistance mutation) [1]. It was designed to combat advanced tumours that are driven by this mutated kinase, whilst sparing function of the wild type EGFR.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 2
Rotatable bonds 11
Topological polar surface area 81.56
Molecular weight 498.62
XLogP 2.53
No. Lipinski's rules broken 0
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Canonical SMILES C=CC(=O)NC1=C(C=CC(=C1)C2=C(C3=CC=CC=C3)OC4=C2C(=NC=N4)NC(C)C)N(C)CCN(C)C
Isomeric SMILES CN(CCN(C)C)C=1C(NC(C=C)=O)=CC(=CC1)C2=C(C3=CC=CC=C3)OC4=C2C(NC(C)C)=NC=N4
InChI InChI=1S/C29H34N6O2/c1-7-24(36)33-22-17-21(13-14-23(22)35(6)16-15-34(4)5)25-26-28(32-19(2)3)30-18-31-29(26)37-27(25)20-11-9-8-10-12-20/h7-14,17-19H,1,15-16H2,2-6H3,(H,33,36)(H,30,31,32)
Bioactivity Comments
Although the selectivity of compound 52 for EGFRL858R/T790M compared to WT EGFR is low in an enzymatic activity assay (1.7-fold), its selectivity is increased in model cells lines [1]. Compound 52 produces an antitumour effect in xenograft models of EGFRL858R/T790M-driven cancer.
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 Inhibitor Inhibition 7.6 – 7.8 pIC50 - 1
pIC50 7.8 (IC50 1.5x10-8 M) [1]
Description: Inhibition of EGFRL858R/T790M enzyme activity
pIC50 7.6 (IC50 2.5x10-8 M) [1]
Description: Inhibition of WT EGFR enzymatic activity