A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor-dependent tumor growth in vivo
A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor-dependent tumor growth in vivo
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DOI：
10.1158/1535-7163.mct-07-0070
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发表时间：
2007-08-01
影响因子：
5.7
通讯作者：
Pachter, Jonathan A.
中科院分区：
文献类型：
--
作者：
Ji, Qun-Sheng;Mulvihill, Mark J.;Pachter, Jonathan A.
胰岛素样生长因子-1受体（IGF-IR）及其配体IGF-I和IGF-II在多种人类癌症中上调。在肿瘤中，如结直肠癌、非小细胞肺癌、卵巢癌和儿科癌症，它们可能通过自分泌IGF-II表达来驱动自身的生长和存活，IGF-IR的作用尤其关键。在此，我们提出了一种新的小分子IGF-IR激酶抑制剂，顺式-3-[13-（4-甲基-哌嗪-1-基）-环丁基]-1-（2-苯基-喹啉-7-基）-咪唑并[1，5-a]吡嗪-8-基胺（PQIP），其对抑制人IGF-IR的配体依赖性自磷酸化的细胞IC 50为19 nmol/L，相对于人胰岛素受体，其细胞选择性为14倍。PQIP对一组32种其他蛋白激酶显示出最小的活性。它还取消了IGF-IR转染细胞和GEO人结直肠癌细胞系中下游磷酸化AKT和磷酸化细胞外信号调节激酶1/2的配体诱导的激活。GEO细胞的分析揭示了磷酸化IGF-IR和IGF-II表达的显著水平。此外，IG-II在条件GEO培养基中的灭活通过中和抗体减少IGF-IR活化，表明GEO细胞中存在功能性IGF-II/IGF-IR自分泌环。每日一次口服给药PQIP在GEO异种移植物中诱导稳健的抗肿瘤功效。抗肿瘤功效与该化合物在体内抑制肿瘤IGF-IR磷酸化的程度和持续时间相关。此外，当用最大程度抑制肿瘤生长的剂量的PQIP治疗小鼠3天时，仅观察到血糖的微小变化。因此，PQIP代表了一种有效的和选择性的IGF-IR激酶抑制剂，其在IGF-II驱动的人肿瘤模型中特别有效。
Insulin-like growth factor-1 receptor (IGF-IR) and its ligands, IGF-I and IGF-II, are up-regulated in a variety of human cancers. In tumors, such as colorectal, non-small cell lung, ovarian, and pediatric cancers, which may drive their own growth and survival through autocrine IGF-II expression, the role of IGF-IR is especially critical. Here, we present a novel small-molecule IGF-IR kinase inhibitor, cis-3-13-(4-methyl-piperazin-1-yl)-cyclobutyll-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP), which displayed a cellular IC50 of 19 nmol/L for inhibition of ligand-dependent autophosphorylation of human IGF-IR with 14-fold cellular selectivity relative to the human insulin receptor. PQIP showed minimal activity against a panel of 32 other protein kinases. It also abolished the ligand-induced activation of downstream phosphorylated AKT and phosphorylated extracellular signal-regulated kinase 1/2 in both IGF-IR transfectant cells and a GEO human colorectal cancer cell line. Analysis of GEO cells revealed a significant level of both phosphorylated IGF-IR and IGF-II expression. Furthermore, inactivation of IG-II in conditioned GEO culture medium by a neutralizing antibody diminished IGF-IR activation, indicating the presence of a functional IGF-II/IGF-IR autocrine loop in GEO cells. Once daily oral dosing of PQIP induced robust antitumor efficacy in GEO xenografts. The antitumor efficacy correlated with the degree and duration of inhibition of tumor IGF-IR phosphorylation in vivo by this compound. Moreover, when mice were treated for 3 days with a dose of PQIP that maximally inhibited tumor growth, only minor changes in blood glucose were observed. Thus, PQIP represents a potent and selective IGF-IR kinase inhibitor that is especially efficacious in an IGF-II-driven human tumor model.