Authors' Affiliation: Exelixis, Inc., South San Francisco, California.
Mol Cancer Ther. 2014 May;13(5):1078-91. doi: 10.1158/1535-7163.MCT-13-0709. Epub 2014 Mar 14.
Activation of the PI3K (phosphoinositide 3-kinase) pathway is a frequent occurrence in human tumors and is thought to promote growth, survival, and resistance to diverse therapies. Here, we report pharmacologic characterization of the pyridopyrimidinone derivative XL765 (SAR245409), a potent and highly selective pan inhibitor of class I PI3Ks (α, β, γ, and δ) with activity against mTOR. Broad kinase selectivity profiling of >130 protein kinases revealed that XL765 is highly selective for class I PI3Ks and mTOR over other kinases. In cellular assays, XL765 inhibits the formation of PIP(3) in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL765 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approximately 24 hours. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is associated with antiproliferative, antiangiogenic, and proapoptotic effects.
PI3K（磷酸肌醇 3-激酶）通路的激活在人类肿瘤中经常发生，被认为可促进生长、存活和对多种治疗方法的耐药性。在这里，我们报告了吡咯并嘧啶酮衍生物 XL765（SAR245409）的药理特性，它是一种有效的、高度选择性的 I 类 PI3K（α、β、γ 和 δ）全抑制剂，对 mTOR 具有活性。对 >130 种蛋白激酶的广泛激酶选择性分析表明，XL765 对 I 类 PI3K 和 mTOR 的选择性高于其他激酶。在细胞测定中，XL765 抑制膜中 PIP(3)的形成，并抑制多种肿瘤细胞系中 AKT、p70S6K 和 S6 磷酸化的磷酸化，这些细胞系具有影响 PI3K 通路的不同遗传改变。在一组肿瘤细胞系中，XL765 以广泛的效力抑制增殖，并且存在基因型对敏感性的影响的证据。在小鼠异种移植模型中，口服 XL765 导致 AKT、p70S6K 和 S6 的磷酸化呈剂量依赖性抑制，作用持续时间约为 24 小时。重复给予 XL765 导致裸鼠中多种人异种移植模型中的肿瘤生长显著抑制，这与抗增殖、抗血管生成和促凋亡作用有关。
