Targeting an EGFR Water Network with 4 Anilinoquin(az)oline Inhibitors for Chordoma
Quinoline and quinazoline based kinase inhibitors of the epidermal growth factor receptor (EGFR) have been used to target non small cell lung cancer (NSCLC) and chordomas with varying amounts of success. We designed and prepared compounds to probe several key structural features including an interaction with Asp855 within the EGFR DGF motif and interactions with the active site water network. EGFR target engagement was then evaluated in a cellular assay, with the inhibitors then profiled in representative cellular models of NSCLC and chordomas. In addition, structure activity relationship insight into EGFR inhibitor design with potent dimethoxyquin(az)olines identified compounds 1 [N (3 ethynylphenyl) 6,7 dimethoxyquinolin 4 amine] 4 [N (3 ethynylphenyl) 6,7 dimethoxyquinazolin 4 amine] and 7 [4 (3 ethynylphenyl)amino) 6,7 dimethoxyquinoline 3 carbonitrile] We also identified 6,7 dimethoxy N (4 (4 methylbenzyl)oxy)phenyl)quinolin 4 amine (compound 18) which is the most potent inhibitor (IC50=310 nm) of the UCH 2 chordoma cell line to date.
ChemMedChem