jm050607w_si_001.pdf (38.72 kB)
Anilinodialkoxyquinazolines: Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Potential Tumor Imaging Probes
journal contributionposted on 2005-11-17, 00:00 authored by Henry F. VanBrocklin, John K. Lim, Stephanie L. Coffing, Darren L. Hom, Kitaw Negash, Michele Y. Ono, Jennifer L. Gilmore, Ianthe Bryant, David J. Riese
The epidermal growth factor receptor (EGFR), a long-standing drug development target, is also a desirable target for imaging. Sixteen dialkoxyquinazoline analogues, suitable for labeling with positron-emitting isotopes, have been synthesized and evaluated in a battery of in vitro assays to ascertain their chemical and biological properties. These characteristics provided the basis for the adoption of a selection schema to identify lead molecules for labeling and in vivo evaluation. A new EGFR tyrosine kinase radiometric binding assay revealed that all of the compounds possessed suitable affinity (IC50 = 0.4−51 nM) for the EGFR tyrosine kinase. All of the analogues inhibited ligand-induced EGFR tyrosine phosphorylation (IC50 = 0.8−20 nM). The HPLC-estimated octanol/water partition coefficients ranged from 2 to 5.5. Four compounds, 4-(2‘-fluoroanilino)- and 4-(3‘-fluoroanilino)-6,7-diethoxyquinazoline as well as 4-(3‘-chloroanilino)- and 4-(3'-bromoanilino)-6,7-dimethoxyquinazoline, possess the best combination of characteristics that warrant radioisotope labeling and further evaluation in tumor-bearing mice.