title: BB, a new EGFR inhibitor, exhibits prominent anti-angiogenesis and antitumor activities.
abstract: Aberrant activation of the epidermal growth factor receptor (EGFR) is closely associated with malignant progression of tumors. EGFR inhibitors have been used successfully in clinic in the treatment of solid tumors. In the present study, we revealed that BB, a new synthetic quinonazoline derivative, was a potent EGFR inhibitor. BB selectively inhibited EGFR with a IC(50) value of 50 +/- 37 nM, at least 32-fold more potent than suppressed all other ten tested receptor tyrosine kinases including the same family member ErbB2 (IC(50) = 5.6 +/- 3.2 microM). BB effectively abrogated autophosphorylation of the EGF-stimulated EGFR and phosphorylation of its key downstream signaling molecules ERK and AKT in A549 cells. BB was shown to suppress EGF-stimulated proliferation of A549 cells with an apparently lower IC(50) value (0.33 +/- 0.07 microM) than that (2.7 +/- 0.4 microM) for the serum-stimulated cells. BB also inhibited the EGF-independent proliferation of a panel of tumor cells. In addition, BB exhibited anti-angiogenesis activity, as evidenced by antagonizing EGF-induced HMEC-1 migration in vitro, blocking HMEC-1 tube formation, and inhibiting microvessel sprouting from rat aortic rings. Most importantly, BB prominently inhibited in vivo tumorigenesis of NIH3T3 cells specifically driven by the activation-mutated EGFR genes. As reported, normal NIH3T3 cells lack tumorigenicity in nude mice. NIH3T3 cells transfected with the EGFR gene with activating mutation (A750P or L858R) produced rapidly growing xenografts in nude mice. BB, when given orally at 100 mg/kg consecutively for 2 w, prominently inhibited the growth of the xenografts and reduced the number of microvessels. Taken together, the data indicate that BB is a new selective EGFR inhibitor with potent antitumor activity, revealing its potential as a promising anticancer candidate.
authors.affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qi-Ming
authors.initials: QM
authors.lastname: Sun
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Lin
authors.forename: Min
authors.initials: M
authors.lastname: Gui
authors.forename: Cai-Hua
authors.initials: CH
authors.lastname: Zhu
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.forename: Wen-Hu
authors.initials: WH
authors.lastname: Duan
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D014162:Transfection
chemical_list: D020533:Angiogenesis Inhibitors; D000814:Aniline Compounds; D000970:Antineoplastic Agents; C539257:N-(3-bromophenyl)-7-methoxy-6-(3-(3-methoxypyrrolidin-1-yl)propoxy)quinazolin-4-amine; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D066246:ErbB Receptors