EAI045 is an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild-type receptor.
EGFR (epidermal growth factor receptor) is a cell-surface receptor tyrosine kinase. The receptor activation leads to dimerization and tyrosine autophosphorylation. It induces a cascade of downstream cellular responses such as modification in gene expression, cell proliferation and cytoskeletal rearrangement etc.
EAI1045 has an IC50 of 3 nM against the L858R/T790M mutant with a 1000-fold selectivity over wild-type EGFR at 1 mM ATP. In combination with 10 μg/ml cetuximab, EAI045 inhibited proliferation of EGFR (L858R/T790M) Ba/F3 cells with an IC50 of approximately 10nM.
In mice treated with EAI045 at 60 mg kg−1 by oral gavage once daily, combined treatment with cetuximab (1 mg intraperitoneally every other day) showed prominent tumour regressions, but these treated with EAI045 alone did not respond to the treatment.
Pharmacodynamic studies in exon19del/T790M and L858R/T790M/C797S mice indicated combined treatment of EAI045 with cetuximab effectively inhibited phosphorylation of EGFR and downstream signalling proteins in those mice, but not in mice with insensitive exon19del/T790M mutation.
Reference:
1. Jia Y, Yun CH, Park E et al.Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature. 2016 May 25;534(7605):129-32.