Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase
Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase
复制标题
DOI：
10.1158/1078-0432.ccr-08-2530
复制
发表时间：
2009-05-01
影响因子：
11.5
通讯作者：
Kumar, Rakesh
中科院分区：
文献类型：
--
作者：
Sabbatini, Peter;Rowand, Jason L.;Kumar, Rakesh
目的：胰岛素样生长因子-I受体(IGF-IR)信号通路失调与多种肿瘤的发生发展有关，包括前列腺癌、结肠癌、乳腺癌、胰腺癌、卵巢癌和肉瘤。抑制IGF-IR活性的药物可能在各种癌症患者的治疗中有用。实验设计：采用激酶试验鉴定一种选择性的IGF-IR活性的小分子抑制剂。该化合物对IGF-IR信号、细胞增殖和细胞周期的影响是通过一组细胞系来确定的。在裸鼠体内生长的人肿瘤异种移植瘤中评价了抗肿瘤活性。结果：GSK1904529A选择性抑制IGFIR和IR，IC(50)S分别为27和25nmol/L。GSK1904529A阻断受体自动磷酸化和下游信号，导致细胞周期停滞。它能抑制实体和血液系统恶性肿瘤细胞系的增殖，其中多发性骨髓瘤和尤文氏肉瘤细胞系最为敏感。口服GSK1904529A可减少小鼠人肿瘤移植瘤的生长，这与肿瘤中IGF-IR磷酸化的减少是一致的。尽管GSK1904529A在体内外对胰岛素抵抗有很强的抑制作用，但在具有显著抗肿瘤活性的剂量下，对动物血糖水平的影响很小。结论：GSK1904529A是一种有前景的治疗IGF-IR依赖性肿瘤的候选药物。
Purpose: Dysregulation of the insulin-like growth factor-I receptor (IGF-IR) signaling pathway has been implicated in the development of many types of tumors, including prostate, colon, breast, pancreatic, ovarian, and sarcomas. Agents that inhibit IGF-IR activity may be useful in treatment of patients with various cancers.Experimental Design: Kinase assays were used to identify a selective small-molecule inhibitor of IGF-IR activity. The effects of this compound on IGF-IR signaling, cell proliferation, and the cell cycle were determined using a panel of cell lines. Antitumor activity was evaluated in human tumor xenografts growing in athymic mice. Inhibition of IGF-IR and the closely related insulin receptor (IR) was measured in vivo, and the effect on glucose metabolism was evaluated.Results: GSK1904529A selectively inhibits IGF-IR and IR with IC(50)s of 27 and 25 nmol/L, respectively. GSK1904529A blocks receptor autophosphorylation and downstream signaling, leading to cell cycle arrest. It inhibits the proliferation of cell lines derived from solid and hematologic malignancies, with multiple myeloma and Ewing's sarcoma cell lines being most sensitive. Oral administration of GSK1904529A decreases the growth of human tumor xenografts in mice, consistent with a reduction of IGF-IR phosphorylation in tumors. Despite the potent inhibitory activity of GSK1904529A on IR in vitro and in vivo, minimal effects on blood glucose levels are observed in animals at doses that show significant antitumor activity.Conclusion: GSK1904529A is a promising candidate for therapeutic use in IGF-IR-dependent tumors.