Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is critically involved in cell migration, spreading and proliferation at the early step of various cancers. Small molecule inhibitors of FAK are effective to inhibit its activation in the process of tumor formation in cell. To better understand biotransformation of FAK inhibitors, this work has investigated in vitro phase I metabolism of inhibitors (namely PF-573228, PF-562271 and PF-03814735) by rat liver microsomes model. Using liquid chromatography - quadrupole time of flight mass spectrometry and tandem mass spectrometry (LC/Q-TOF/MS and MS/MS), three metabolites of PF-573228 and PF-562271 were observed and characterized, respectively. These in vitro metabolites were reported for the first time. The structures and fragmentation patterns of these metabolites were elucidated, and phase I metabolic pathways for FAK inhibitors were proposed. The main metabolic pathways of PF-573228 were hydroxylation, dehydrogenation and N-dealkylation. For PF-562271, they were hydroxylation and dehydrogenation. Hydroxylation was observed as the primary metabolism for PF-0381473.

粘着斑激酶（FAK）是一种非受体酪氨酸激酶，在各种癌症的早期阶段都至关重要地参与细胞迁移，扩散和增殖。FAK的小分子抑制剂可有效抑制其在细胞中肿瘤形成过程中的活化。为了更好地了解FAK抑制剂的生物转化，这项工作已通过大鼠肝微粒体模型研究了抑制剂（即PF-573228，PF-562271和PF-03814735）的体外I期代谢。使用液相色谱-四极杆飞行时间质谱和串联质谱（LC / Q-TOF / MS和MS / MS），分别观察和表征了PF-573228和PF-562271的三种代谢物。这些体外首次报道了代谢产物。阐明了这些代谢物的结构和片段化模式，并提出了FAK抑制剂的I期代谢途径。PF-573228的主要代谢途径是羟基化，脱氢和N-脱烷基。对于PF-562271，它们是羟基化和脱氢。观察到羟基化是PF-0381473的主要代谢。