Novel quinazoline derivatives exhibit antitumor activity by inhibiting JAK2/STAT3
Novel quinazoline derivatives exhibit antitumor activity by inhibiting JAK2/STAT3
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DOI：
10.3892/or.2015.4140
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发表时间：
2015-10-01
期刊：
影响因子：
4.2
通讯作者：
Li, Erguang
中科院分区：
文献类型：
--
作者：
Qiao, Haishi;Zhao, Dan;Li, Erguang
含喹唑啉核的化合物如吉非替尼和厄洛替尼构成了一组重要的抗肿瘤药物，其作为受体酪氨酸激酶抑制剂对抗表皮生长因子受体（EGFR）激酶活性。我们研究了一组最近合成的2-烷基取代喹唑啉（2-ASQ）对非小细胞肺癌（NSCLC）细胞的抗肿瘤活性。化合物对A549、H1299和H460细胞具有诱导凋亡的抗肿瘤活性。（E）-2-丙基-4-苯乙烯基喹唑啉（化合物#4）和（E）-2-环丙基-4-苯乙烯基喹唑啉（化合物#7）对这些细胞系的IC 50值比吉非替尼低2-5倍。与阻断EGFR磷酸化的吉非替尼不同，这些化合物对EGFR活化没有活性。相反，这些化合物抑制JAK 2/STAT 3磷酸化和下游基因表达的组成性和IL-6诱导的激活。STAT 3的组成型活性突变体的瞬时表达逆转了化合物#7的促凋亡作用。使用携带A549异种移植物的裸鼠模型，我们表明以15和30 mg/kg施用#7抑制肿瘤生长。因此，本研究表明，2-烷基取代的喹唑啉靶向JAK 2/STAT 3途径的抗肿瘤活性。
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-alkylsubstituted 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-propy1-4-styrylquinazoline (compound #4) and (E)-2-cyclopropy1-4-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.