Dialkoxyquinazolines: Screening Epidermal Growth Factor ReceptorTyrosine Kinase Inhibitors for Potential Tumor Imaging Probes

• Published in: Journal of medicinal chemistry 2005-09, Vol.48 (23)
• Main Authors: VanBrocklin, Henry F., Lim, John K., Coffing, Stephanie L., Hom,Darren L., Negash, Kitaw, Ono, Michele Y., Hanrahan, Stephen M., Taylor,Scott E., Vanderpoel, Jennifer L., Slavik, Sarah M., Morris, Andrew B., Riese II, David J.
• Format: Article
• Language: English
• Subjects: 62; AFFINITY; EGFR Tumor Imaging Kinase Inhibitors; EVALUATION; GROWTH FACTORS; IN VITRO; IN VIVO; MICE; NEOPLASMS; PHOSPHORYLATION; PHOSPHOTRANSFERASES; PROBES; RADIOISOTOPES; TARGETS; TYROSINE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050607w

The epidermal growth factor receptor (EGFR), a long-standingdrug development target, is also a desirable target for imaging. Sixteendialkoxyquinazoline analogs, suitable for labeling with positron-emittingisotopes, have been synthesized and evaluated in a battery of in vitroassays to ascertain their chemical and biological properties. Thesecharacteristics provided the basis for the adoption of a selection schemato identify lead molecules for labeling and in vivo evaluation. A newEGFR tyrosine kinase radiometric binding assay revealed that all of thecompounds possessed suitable affinity (IC50 = 0.4 - 51 nM) for the EGFRtyrosine kinase. All of the analogs inhibited ligand-induced EGFRtyrosine phosphorylation (IC50 = 0.8 - 20 nM). The HPLC-estimatedoctanol/water partition coefficients ranged from 2.0-5.5. Four compounds,4-(2'-fluoroanilino)- and 4-(3'-fluoroanilino)-6,7-diethoxyquinazoline aswell as 4-(3'-chloroanilino)- and4-(3'-bromoanilino)-6,7-dimethoxyquinazoline, possess the bestcombination of characteristics that warrant radioisotope labeling andfurther evaluation in tumor-bearing mice.