Lorlatinib (PF-6463922)
中文名称：劳拉替尼
Lorlatinib (PF-6463922)是一个强效的，双重 ALK/ROS1 的抑制剂，对ROS1, ALK (WT), 以及ALK (L1196M)的Ki分别为<0.02 nM, <0.07 nM, 和0.7 nM。PF-06463922 可诱导凋亡。Phase 1。
Lorlatinib (PF-6463922) Chemical Structure
CAS: 1454846-35-5
产品质控
批次：
纯度：
99.95%
99.95
Lorlatinib (PF-6463922)相关产品
相关信号通路图
细胞实验数据示例
| 细胞系 | 实验类型 | 给药浓度 | 孵育时间 | 活性描述 | 文献信息 |
|---|---|---|---|---|---|
| NIH-3T3 | Function assay | 1 hr | 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, IC50 = 0.0002 μM. | 24819116 | |
| BAF3 | Antiproliferative assay | 72 hrs | Antiproliferative activity against mouse BAF3 cells harboring CD74-ROS1 after 72 hrs by SRB or CCK8 assay, IC50 = 0.0012 μM. | 29288940 | |
| NIH-3T3 | Function assay | 1 hr | Inhibition of wild type human EML4-fused ALK expressed in mouse NIH-3T3 cells assessed as phosphorylated ALK level after 1 hr by sandwich ELISA, IC50 = 0.0013 μM. | 24819116 | |
| NIH-3T3 | Function assay | 1 hr | Inhibition of human EML4-fused ALK C1156Y mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.0016 μM. | 24819116 | |
| BAF3 | Antiproliferative assay | 72 hrs | Antiproliferative activity against mouse BAF3 cells harboring EML4-ALK after 72 hrs by SRB or CCK8 assay, IC50 = 0.0029 μM. | 29288940 | |
| KARPAS299 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human KARPAS299 cells harboring NPM-ALK after 72 hrs by SRB or CCK8 assay, IC50 = 0.003 μM. | 29288940 | |
| NIH-3T3 | Function assay | 1 hr | Inhibition of human EML4-fused ALK S1206Y mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.0042 μM. | 24819116 | |
| SU-DHL1 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human SU-DHL1 cells harboring NPM-ALK after 72 hrs by SRB or CCK8 assay, IC50 = 0.0049 μM. | 29288940 | |
| NCI-H3122 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human NCI-H3122 cells after 72 hrs by SRB or CCK8 assay, IC50 = 0.0078 μM. | 29288940 | |
| NIH-3T3 | Function assay | 1 hr | Inhibition of human EML4-fused ALK L1152R mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.009 μM. | 24819116 | |
| NIH-3T3 | Function assay | 1 hr | Inhibition of human EML4-fused ALK G1269A mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.015 μM. | 24819116 | |
| NIH-3T3 | Function assay | 1 hr | Inhibition of human EML4-fused ALK L1196M mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.021 μM. | 24819116 | |
| NIH-3T3 | Function assay | 1 hr | Inhibition of human EML4-fused ALK 1151Tins mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.038 μM. | 24819116 | |
| BAF3 | Antiproliferative assay | 72 hrs | Antiproliferative activity against mouse BAF3 cells harboring EML4-ALK L1196M mutant after 72 hrs by SRB or CCK8 assay, IC50 = 0.0424 μM. | 29288940 | |
| NIH-3T3 | Function assay | 1 hr | Inhibition of human EML4-fused ALK G1202R mutant expressed in mouse NIH-3T3 cells assessed as phospho-ALK level after 1 hr by sandwich ELISA, IC50 = 0.077 μM. | 24819116 | |
| BAF3 | Antiproliferative assay | 72 hrs | Antiproliferative activity against mouse BAF3 cells harboring EML4-ALK G1202R mutant after 72 hrs by SRB or CCK8 assay, IC50 = 0.2 μM. | 29288940 | |
| BAF3 | Antiproliferative assay | 72 hrs | Antiproliferative activity against mouse BAF3 cells harboring CD74-ROS1 G2032R mutant after 72 hrs by SRB or CCK8 assay, IC50 = 0.262 μM. | 29288940 | |
| HCC78 | Antiproliferative assay | 72 hrs | Antiproliferative activity against human HCC78 cells harboring SLC34A2-ROS1 after 72 hrs by SRB or CCK8 assay, IC50 = 0.357 μM. | 29288940 | |
| NIH/3T3 | Function assay | Inhibition of wild type EML4/ALK F1174L mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.0002 μM. | 28431340 | ||
| NIH/3T3 | Function assay | Inhibition of wild type EML4/ALK (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.0013 μM. | 28431340 | ||
| NIH/3T3 | Function assay | Inhibition of wild type EML4/ALK C1156Y mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.0016 μM. | 28431340 | ||
| NIH/3T3 | Function assay | Inhibition of wild type EML4/ALK S1206Y mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.0042 μM. | 28431340 | ||
| NIH/3T3 | Function assay | Inhibition of wild type EML4/ALK L1152R mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.009 μM. | 28431340 | ||
| NIH/3T3 | Function assay | Inhibition of wild type EML4/ALK G1269A mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.015 μM. | 28431340 | ||
| NIH/3T3 | Function assay | Inhibition of wild type EML4/ALK L1196M mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.021 μM. | 28431340 | ||
| NIH/3T3 | Function assay | Inhibition of wild type EML4/ALK 1151Tins mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.038 μM. | 28431340 | ||
| NIH/3T3 | Function assay | Inhibition of wild type EML4/ALK G1202R mutant (unknown origin) expressed in NIH/3T3 cells, IC50 = 0.077 μM. | 28431340 | ||
| SU-DHL1 | Function assay | Inhibition of ALK in human SU-DHL1 cells assessed as reduction in STAT3 phosphorylation at Y705 residue at 20 to 80 nM after 1 hr by Western blot analysis | 29288940 | ||
| SU-DHL1 | Function assay | Inhibition of ALK in human SU-DHL1 cells assessed as reduction in Akt phosphorylation at S473 residue at 20 to 80 nM after 1 hr by Western blot analysis | 29288940 | ||
| SU-DHL1 | Function assay | Inhibition of ALK phosphorylation at Y1278 residue in human SU-DHL1 cells at 20 to 80 nM after 1 hr by Western blot analysis | 29288940 | ||
| SU-DHL1 | Function assay | Inhibition of ALK in human SU-DHL1 cells assessed as reduction in ERK phosphorylation at T202//Y204 residues at 20 to 80 nM after 1 hr by Western blot analysis | 29288940 | ||
| NCI-H3122 | Function assay | Inhibition of ALK phosphorylation at Y1278 residue in human NCI-H3122 cells at 20 to 80 nM after 1 hr by Western blot analysis | 29288940 | ||
| NCI-H3122 | Function assay | Inhibition of ALK in human NCI-H3122 cells assessed as reduction in STAT3 phosphorylation at Y705 residue at 20 to 80 nM after 1 hr by Western blot analysis | 29288940 | ||
| NCI-H3122 | Function assay | Inhibition of ALK in human NCI-H3122 cells assessed as reduction in Akt phosphorylation at S473 residue at 20 to 80 nM after 1 hr by Western blot analysis | 29288940 | ||
| NCI-H3122 | Function assay | Inhibition of ALK in human NCI-H3122 cells assessed as reduction in ERK phosphorylation at T202//Y204 residues at 20 to 80 nM after 1 hr by Western blot analysis | 29288940 | ||
| 点击查看更多细胞系数据 | |||||
生物活性
| 产品描述 | Lorlatinib (PF-6463922)是一个强效的，双重 ALK/ROS1 的抑制剂，对ROS1, ALK (WT), 以及ALK (L1196M)的Ki分别为<0.02 nM, <0.07 nM, 和0.7 nM。PF-06463922 可诱导凋亡。Phase 1。 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 靶点 |
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| 体外研究(In Vitro) | ||||
| 体外研究活性 | PF-06463922对ALK和大量ALK临床突变型表现出显著的细胞活性，IC50范围为0.2 nM-77 nM。[1]在含有SLC34A2-ROS1 融合物的HCC78人NSCLC细胞和表达人CD74-ROS1的BaF3-CD74-ROS1细胞中，PF-06463922显著抑制细胞增殖，并诱导细胞凋亡。[2] 在含有非突变型ALK或突变型ALK融合物的NSCLC 细胞中，PF-06463922也表现出有效的生长抑制活性，并诱导细胞凋亡。[3] | |||
|---|---|---|---|---|
| 实验图片 | 检测方法 | 检测指标 | 实验图片 | PMID |
| Western blot | p-ALK / ALK |
|
29650534 | |
| 体内研究(In Vivo) | ||
| 体内研究活性 | 在大鼠体内，PF-06463922显示出低血浆清除率，适度的分布容积，合理的半衰期，对低P-糖蛋白1介导的外排敏感性低，且生物利用度为100%。[1]在体内，表达人CD74-ROS1 和 Fig-ROS1的NIH3T3异种移植模型中，PF-06463922表现出细胞减少性抗癌作用，通过抑制ROS1磷酸化和下游信号分子，以及对肿瘤中细胞周期蛋白D1的抑制发挥作用。[2]在负荷肿瘤移植物，过表达EML4-ALK，EML4-ALK-L1196M，EML4-ALK-G1269A，EML4-ALK-G1202R 或NPM-ALK的小鼠体内，PF-06463922也表现出显著的抗肿瘤活性。[3] | |
|---|---|---|
| NCT Number | Recruitment | Conditions | Sponsor/Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT06378892 | Recruiting | Non Small Cell Lung Cancer Metastatic|ALK Gene Mutation |
Centro di Riferimento Oncologico - Aviano |
March 15 2024 | Phase 2 |
| NCT06092086 | Recruiting | ALK Positive Non-small Cell Lung Cancer |
Guangdong Association of Clinical Trials |
August 18 2023 | Phase 2 |
| NCT05297890 | Active not recruiting | Advanced or Metastatic ROS1-Positive Non-Small Cell Lung Cancer |
CStone Pharmaceuticals|Pfizer |
May 27 2022 | Phase 2 |
| NCT05224609 | Recruiting | Moderate Hepatic Impairment|Severe Hepatic Impairment|Healthy Volunteers |
Pfizer |
April 28 2022 | Phase 1 |
化学信息&溶解度
| 分子量 | 406.41 | 分子式 | C21H19FN6O2 |
| CAS号 | 1454846-35-5 | SDF | Download Lorlatinib (PF-6463922) SDF |
| Smiles | CC1C2=C(C=CC(=C2)F)C(=O)N(CC3=NN(C(=C3C4=CC(=C(N=C4)N)O1)C#N)C)C | ||
| 储存条件(自收到货起) | |||
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体外溶解度 |
DMSO : 81 mg/mL ( (199.3 mM) ；DMSO吸湿会降低化合物溶解度，请使用新开封DMSO) Ethanol : 40.5 mg/mL (99.65 mM) Water : Insoluble |
摩尔浓度计算器 |
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体内溶解配方 现配现用，请按从左到右的顺序依次添加，澄清后再加入下一溶剂 |
动物体内配方计算器 | |||||
实验计算
动物体内配方计算器（澄清溶液）
第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量）
mg/kg
g
μL
只
第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系Selleck为您提供正确的澄清溶液配方）
% DMSO
%
% Tween 80
% ddH2O
%DMSO
%
计算结果：
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于μL DMSO溶液（母液浓度mg/mL，注：如该浓度超过该批次药物DMSO溶解度，请先联系Selleck）；
体内配方配制方法：取μL DMSO母液，加入μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入μL ddH2O，混匀澄清。
体内配方配制方法：取μL DMSO母液，加入μL Corn oil，混匀澄清。
注意：1. 首先保证母液是澄清的；
2.一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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常见问题及建议解决方法
问题 1:
Do you have any special suggestions for solution of S7536, Lorlatinib (PF-6463922) to be applied to mouse models?
回答：
For S7536, we recommend 2% DMSO+30% PEG 300+ddH2O (up to 5mg/ml) for in vivo application.
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