ALK (anaplastic lymphoma kinase) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification or point mutation. Lorlatinib is a dual inhibitor of ALK and ROS1 with Ki values of 2nM, 7nM and 70nM for ROS1, ALK and ALK-L1196M (measured by kinase screening assays). Cellular study showed that Lorlatinib possessed a more potent kinase inhibitory effect on EML4-ALK mutation, compared with Crizotinib, with IC50 values on p-ALK of 1.3nM, 0.2nM, 1.6nM, 15nM, 4.2nM, 21nM, 9nM, 77nM and 38nM for different mutations ALK, F1174L, C1156Y, G1269A, S1206Y, L1196M, L1152R, G1202R and 1151Tins in 3T3-EML4-ALK engineered cell lines[1]. As a dual inhibitor, Lorlatinib also showed potency to block crizotinib-resistant ROS1 mutations. In vitro study showed that Lorlatinib exhibited subnanomolar IC50 values of ranging in 0.19–0.53nM against pROS1-Tyr2274 in a panel of NIH 3T3 and BaF3 cells engineered to express selected oncogenic ROS1 fusion variants including CD74-ROS1, SLC34A2-ROS1, and FIGROS1. Also, it inhibited the crizotinib-refractory ROS1-G2032R mutation and the ROS1-G2026M gatekeeper mutation. In vivo studies showed that Lorlatinib markedly inhibit the tumor growth in models expressing FIG-ROS1 (1, 3mg/kg), CD74-ROS1 (0.2-6mg/kg) and the CD74-ROS1-G2032R (3-60mg/kg) mutation[2]. In addition, Lorlatinib is designed for CNS availability for a single 10mg/kg oral dose of this compound achieved its distributes into the CNS in rat[1]. Lorlatinib at dose of 10mg/kg (but administered by s.c. osmotic pumps) demonstrated the antitumor activity in a genetically engineered mouse model of FIG-ROS1 glioblastoma[2].
作用机制
Lorlatinib is an ATP-competitive small-molecule inhibitor.[2]
Lorlatinib 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
mouse NIH-3T3 cells
Function assay
1 h
Inhibition of human EML4-fused ALK F1174L mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA
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