Pappano William N, Jung Paul M, Meulbroek Jonathan A, Wang Yi-Chun, Hubbard Robert D, Zhang Qian, Grudzien Meagan M, Soni Niru B, Johnson Eric F, Sheppard George S, Donawho Cherrie, Buchanan Fritz G, Davidsen Steven K, Bell Randy L, Wang Jieyi
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
BMC Cancer. 2009 Sep 4;9:314. doi: 10.1186/1471-2407-9-314.
The insulin-like growth factor (IGF) axis is an important signaling pathway in the growth and survival of many cell and tissue types. This pathway has also been implicated in many aspects of cancer progression from tumorigenesis to metastasis. The multiple roles of IGF signaling in cancer suggest that inhibition of the pathway might yield clinically effective therapeutics.
We describe A-928605, a novel pyrazolo [3,4-d]pyrimidine small molecule inhibitor of the receptor tyrosine kinases (IGF1R and IR) responsible for IGF signal transduction. This compound was first tested for its activity and selectivity via conventional in vitro kinome profiling and cellular IGF1R autophosphorylation. Additionally, cellular selectivity and efficacy of A-928605 were analyzed in an IGF1R oncogene-addicted cell line by proliferation, signaling and microarray studies. Finally, in vivo efficacy of A-928605 was assessed in the oncogene-addicted cell line and in a neuroblastoma model as a single agent as well as in combination with clinically approved therapeutics targeting EGFR in models of pancreatic and non-small cell lung cancers.
A-928605 is a selective IGF1R inhibitor that is able to abrogate activation of the pathway both in vitro and in vivo. This novel compound dosed as a single agent is able to produce significant growth inhibition of neuroblastoma xenografts in vivo. A-928605 is also able to provide additive effects when used in combination with clinically approved agents directed against EGFR in non-small cell lung and human pancreatic tumor models.
These results suggest that a selective IGF1R inhibitor such as A-928605 may provide a useful clinical therapeutic for IGF pathway affected tumors and warrants further investigation.
胰岛素样生长因子（IGF）轴是许多细胞和组织类型生长与存活中的重要信号通路。该通路也与癌症从肿瘤发生到转移的多个进展阶段相关。IGF信号在癌症中的多种作用表明，抑制该通路可能产生临床有效的治疗方法。
我们描述了A-928605，一种新型的吡唑并[3,4-d]嘧啶小分子抑制剂，可抑制负责IGF信号转导的受体酪氨酸激酶（IGF1R和IR）。该化合物首先通过传统的体外激酶组分析和细胞IGF1R自磷酸化检测其活性和选择性。此外，通过增殖、信号传导和微阵列研究，在IGF1R癌基因成瘾细胞系中分析了A-928605的细胞选择性和功效。最后，在癌基因成瘾细胞系和神经母细胞瘤模型中评估了A-928605作为单一药物以及与临床批准的靶向EGFR的治疗药物联合用于胰腺癌和非小细胞肺癌模型时的体内疗效。
A-928605是一种选择性IGF1R抑制剂，能够在体外和体内消除该通路的激活。这种新型化合物作为单一药物给药能够在体内对神经母细胞瘤异种移植产生显著的生长抑制作用。在非小细胞肺癌和人胰腺癌模型中，A-928605与临床批准的针对EGFR的药物联合使用时也能够产生相加效应。
这些结果表明，像A-928605这样的选择性IGF1R抑制剂可能为受IGF通路影响的肿瘤提供一种有用的临床治疗方法，值得进一步研究。
