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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.
AuthorsHaishi Qiao, Dan Zhao, Hengfei Shi, Ke Ren, Jianxin Li, Erguang Li
JournalOncology reports (Oncol Rep) Vol. 34 Issue 4 Pg. 1875-82 (Oct 2015) ISSN: 1791-2431 [Electronic] Greece
PMID26238612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Quinazolines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Erlotinib Hydrochloride
  • EGFR protein, human
  • ErbB Receptors
  • JAK2 protein, human
  • Janus Kinase 2
  • Gefitinib
Topics
  • Animals
  • Apoptosis (drug effects)
  • Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
  • Cell Line, Tumor
  • ErbB Receptors (biosynthesis, genetics)
  • Erlotinib Hydrochloride (administration & dosage)
  • Gefitinib
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Janus Kinase 2 (antagonists & inhibitors, biosynthesis, genetics)
  • Mice
  • Quinazolines (administration & dosage)
  • STAT3 Transcription Factor (antagonists & inhibitors, biosynthesis, genetics)
  • Signal Transduction (drug effects)
  • Xenograft Model Antitumor Assays

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