title: Novel quinazoline derivatives exhibit antitumor activity by inhibiting JAK2/STAT3.
abstract: Quinazoline core-containing compounds such as gefitinib and erlotinib constitute an important group of antitumor drugs that act as receptor tyrosine kinase inhibitors against epidermal growth factor receptor (EGFR) kinase activity. We investigated a group of recently prepared 2-alkyl-substituted quinazolines (2-ASQs) for their antitumor activity against non-small cell lung carcinoma (NSCLC) cells. The compounds showed antitumor activity against A549, H1299, and H460 cells by induction of apoptosis. The IC50 values for (E)-2-propyl-4-styrylquinazoline (compound #4) and (E)-2‑cyclopropyl-4-styrylquinazoline (compound #7) against these cell lines were 2-5 times lower than that of gefitinib. Unlike gefitinib that blocks EGFR phosphorylation, these compounds showed no activity against EGFR activation. Instead, the compounds suppressed both constitutive and IL-6-induced activation of JAK2/STAT3 phosphorylation and downstream gene expression. Transient expression of a constitutively active mutant of STAT3 reversed the pro-apoptotic effect of compound #7. Using a nude mouse model bearing A549 xenografts, we showed that administration of #7 at 15 and 30 mg/kg suppressed tumor growth. The present study therefore demonstrated that 2-alkyl substituted quinazolines target the JAK2/STAT3 pathway for their antitumor activity.
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Haishi
authors.initials: H
authors.lastname: Qiao
authors.affiliation: School of Chemistry and Chemical Engineering and State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Hengfei
authors.initials: H
authors.lastname: Shi
authors.affiliation: Jiangsu Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.affiliation: School of Chemistry and Chemical Engineering and State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Li
authors.affiliation: Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu 210093, P.R. China.
authors.forename: Erguang
authors.initials: E
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D011799:Quinazolines / Q000008:administration & dosage*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D011799:Quinazolines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D000077156:Gefitinib