Foster Paul, Yamaguchi Kyoko, Hsu Pin P, Qian Fawn, Du Xiangnan, Wu Jianming, Won Kwang-Ai, Yu Peiwen, Jaeger Christopher T, Zhang Wentao, Marlowe Charles K, Keast Paul, Abulafia Wendy, Chen Jason, Young Jenny, Plonowski Artur, Yakes F Michael, Chu Felix, Engell Kelly, Bentzien Frauke, Lam Sanh T, Dale Stephanie, Yturralde Olivia, Matthews David J, Lamb Peter, Laird A Douglas
Exelixis, Inc., South San Francisco, California.
Mol Cancer Ther. 2015 Apr;14(4):931-40. doi: 10.1158/1535-7163.MCT-14-0833. Epub 2015 Jan 30.
Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents.
PI3K/PTEN信号通路组分失调导致PI3K信号过度激活，这在多种癌症中经常被观察到，并且与肿瘤生长和存活相关。对包括受体酪氨酸激酶（RTK）抑制剂和化疗药物在内的多种抗癌疗法产生耐药性，被认为是由于PI3K/PTEN信号通路中下调信号的缺失或减弱。因此，PI3K抑制剂作为单一药物或与其他疗法联合使用，对多种癌症适应症具有治疗潜力。XL147（SAR245408）是一种强效且高度选择性的I类PI3K（α、β、γ和δ）抑制剂。此外，对超过130种蛋白激酶进行的广泛激酶选择性分析表明，XL147对I类PI3K的选择性高于其他激酶。在细胞实验中，XL147抑制膜中PIP3的形成，并抑制多种肿瘤细胞系中AKT、p70S6K和S6的磷酸化，这些细胞系具有影响PI3K通路的不同基因改变。在一组肿瘤细胞系中，XL147以广泛的效力抑制增殖，有证据表明基因型对敏感性有影响。在小鼠异种移植模型中，口服XL147可导致AKT、p70S6K和S6磷酸化的剂量依赖性抑制，作用持续时间至少为24小时。重复给药XL147可在裸鼠的多种人异种移植模型中显著抑制肿瘤生长。将XL147与化疗药物联合使用，在异种移植模型中产生的抗肿瘤活性比相应单一药物观察到的活性增强。
