生物活性

• 靶点

  ALK Ki:0.07nM

  ALK (L1196M) Ki:0.7nM

  Ros1 Ki:0.02nM

• 描述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]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  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	24819116

• 动物研究
  剂量	Mice: 0.3 mg/kg - 10 mg/kg BID[3] (p.o., BID), 6 mg/kg - 12 mg/kg[3] (s.c.), 1 mg/kg - 60 mg/kg[2] (s.c.)
  给药途径	p.o., s.c.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03737994	ALK Gene Rearrangement ... more >> ALK Positive Non-Squamous Non-Small Cell Lung Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Collapse <<	Phase 2	Not yet recruiting	December 13, 2025	-
  NCT03727477	-	-	Not yet recruiting	December 2020	France ... more >> Paris - Curie Paris, France Collapse <<
  NCT03542305	Renal Impairment	Phase 1	Recruiting	April 11, 2020	United States, California ... more >> Anaheim Clinical Trials, LLC Recruiting Anaheim, California, United States, 92801 United States, Minnesota Prism Clinical Research, LLC Recruiting Saint Paul, Minnesota, United States, 55114 Collapse <<

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