Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271
Antitumor activity and pharmacology of a selective focal adhesion kinase inhibitor, PF-562,271
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DOI：
10.1158/0008-5472.can-07-5155
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发表时间：
2008-03-15
期刊：
影响因子：
11.2
通讯作者：
Vajdos, Felix
中科院分区：
文献类型：
--
作者：
Roberts, Walter Gregory;Ung, Ethan;Vajdos, Felix
癌细胞的特征在于以不依赖于锚定的方式生长的能力。非受体酪氨酸激酶，粘着斑激酶（FAK）的活性被认为有助于这种表型。FAK定位于粘着斑中，并作为其他粘附分子的支架和信号蛋白发挥作用。最近的研究表明FAK表达和磷酸化状态的增加与侵袭性人类肿瘤的侵袭性表型之间有很强的相关性。PF-562，271是FAK和Pyk 2催化活性的强效ATP竞争性可逆抑制剂，IC 50分别为1.5和14 nmol/L。此外，PF-562，271在测量磷酸化FAK的诱导型细胞试验中显示出稳健的抑制作用，IC 50为5 nmol/L。PF-562，271针对多种激酶进行了评价，对一长串非靶标激酶显示出> 100倍的选择性。PF-562，271在体内以剂量依赖性方式抑制FAK磷酸化（计算的EC 50为93 ng/mL，总计）。给药至荷瘤小鼠。FAK磷酸化的体内抑制（>50%）用单次p.o.剂量为33 mg/kg。在多个人s.c.异种移植模型。在任何体内实验中均未观察到体重减轻、发病或死亡。肿瘤生长抑制具有剂量和药物暴露依赖性。总之，这些数据表明，FAK的ATP竞争性小分子抑制剂的激酶抑制降低了体内磷酸化状态，导致稳健的抗肿瘤活性。
Cancer cells are characterized by the ability to grow in an anchorage-independent manner. The activity of the nonreceptor tyrosine kinase, focal adhesion kinase (FAK), Is thought to contribute to this phenotype. FAK localizes in focal adhesion plaques and has a role as a scaffolding and signaling protein for other adhesion molecules. Recent studies show a strong correlation between increased FAK expression and phosphorylation status and the invasive phenotype of aggressive human tumors. PF-562,271 is a potent, ATP-competitive, reversible inhibitor of FAK and Pyk2 catalytic activity with a IC50 of 1.5 and 14 nmol/L, respectively. Additionally, PF-562,271 displayed robust inhibition in an inducible cell-based assay measuring phospho-FAK with an IC50 of 5 nmol/L. PF-562,271 was evaluated against multiple kinases and displays >100X selectivity against a long list of nontarget kinases. PF-562,271 inhibits FAK phosphorylation in vivo in a dose-dependent fashion (calculated EC50 of 93 ng/mL, total) after p.o. administration to tumor-bearing Mice. In vivo inhibition of FAK phosphorylation (>50%) was sustained for >4 hours with a single p.o. dose of 33 mg/kg. Antitumor efficacy and regressions were observed in multiple human s.c. xenograft models. No weight loss, morbidity, or mortality were observed in any in vivo experiment. Tumor growth inhibition was dose and drug exposure dependent. Taken together, these data show that kinase inhibition wit, h an ATP-competitive small molecule inhibitor of FAK decreases the phospho-status in vivo, resulting in robust antitumor activity.