Irreversible inhibition of epidermal growth factor receptor tyrosine kinase with In Vivo activity by N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (CL-387,785)

摘要: Abstract It has been shown previously that 4-anilino quinazolines compete with the ability of ATP to bind epidermal growth factor receptor (EGF-R), inhibit EGF-stimulated autophosphorylation tyrosine residues in EGF-R, and block EGF-mediated growth. Since millimolar concentrations cells could reduce efficacy activity these compounds would not be sustained once they were removed from body, we reasoned irreversible inhibitors EGF-R might improve this series animals. Molecular modeling kinase domain was used design inhibitors. We herein describe one such inhibitor: N -[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide, known as CL-387,785. This compound covalently bound EGF-R. also specifically inhibited protein ( ic 50 = 370 ± 120 pM), blocked ≅ 5 nM), cell proliferation 31–125 nM) primarily a cytostatic manner lines overexpress or c-erbB-2, profoundly tumor overexpresses nude mice (when given orally at 80 mg/kg/day for 10 days, daily). conclude CL-387,785 is useful studying interaction small molecules may have clinical utility.