Centre for Genetics and Inherited Diseases, Taibah University, Al-Madinah Al-Munawwarah, Kingdom of Saudi Arabia.
Department of Chemistry, Allama Iqbal Open University, Islamabad 44000, Pakistan.
Eur J Med Chem. 2017 Jul 7;134:348-356. doi: 10.1016/j.ejmech.2017.04.032. Epub 2017 Apr 13.
Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to 2-generation ALK inhibitors. Lorlatinib (PF-06463922) (6) is a 3-generation macrocyclic ALK-TKI that demonstrates many advantages over 2-generation ALK inhibitors. Lorlatinib has demonstrated decent kinase selectivity, promising pharmacokinetic profile, selective brain-penetration and strong antiproliferative activity in several ALK/ROS1-driven tumor models. The current review describes the activity spectrum, key events from discovery to clinical applications and the evidences that lorlatinib acts as an ALK/ROS1 inhibitor in clinical settings.
非小细胞肺癌（NSCLC）中存在间变性淋巴瘤激酶（ALK）基因重排的患者，对 2 代 ALK 抑制剂不可避免地会产生耐药性。洛拉替尼（PF-06463922）（6）是一种 3 代大环 ALK-TKI，与 2 代 ALK 抑制剂相比具有许多优势。洛拉替尼具有良好的激酶选择性、有前景的药代动力学特征、选择性脑渗透和在多种 ALK/ROS1 驱动的肿瘤模型中具有强大的抗增殖活性。本综述描述了洛拉替尼的作用谱、从发现到临床应用的关键事件，以及洛拉替尼在临床环境中作为 ALK/ROS1 抑制剂的证据。
