| CAS |
No.1454846-35-5 |
| 中文名称 |
劳拉替尼 |
| 英文名称 |
Lorlatinib |
| 别名 |
;PF-06463922，CAS#1454846-35-5，ALK抑制剂;DeoxycytidylicAcidHydrate; |
| 分子式 |
C21H19FN6O2 |
| 分子量 |
406.41 |
| 溶解性 |
Soluble in DMSO(Need ultrasonic) |
| 纯度 |
≥98% |
| 外观(性状) |
Solid |
| 储存条件 |
Powder:2-8℃，2 years;Insolvent(母液):-20℃，6 months;-80℃，1 year |
| MDL |
MFCD28144520 |
| SMILES |
C[C@@H]1C2=C(C=CC(=C2)F)C(=O)N(CC3=NN(C(=C3C4=CC(=C(N=C4)N)O1)C#N)C)C |
| InChIKey |
IIXWYSCJSQVBQM-LLVKDONJSA-N |
| InChI |
InChI=1S/C21H19FN6O2/c1-11-15-7-13(22)4-5-14(15)21(29)27(2)10-16-19(17(8-23)28(3)26-16)12-6-18(30-11)20(24)25-9-12/h4-7，9，11H，10H2，1-3H3，(H2，24，25)/t11-/m1/s1 |
| PubChem CID |
71731823 |
| 靶点 |
ALK;ROS1 |
| 通路 |
Protein Tyrosine Kinase/RTK |
| 背景说明 |
Lorlatinib是一种选择性和 ATP 竞争性的 ROS1/ALK 抑制剂。 |
| 生物活性 |
Lorlatinib (PF-06463922) is a selective， orally active， brain-penetrant and ATP-competitive ROS1/ALK inhibitor with anticancer activity. Lorlatinib has Kis of L1196M， respectively. Lorlatinib targets to EML4-ALK， and inhibits ALK phosphorylation with IC50s of 15-43 nM (ALKL1196)， 14-80 nM (ALKG1269A)， 38-50 nM (ALK1151Tins)， 77-113 nM (ALKG1202R)， respectively.[1-3] |
| IC50 |
IC50: 15-43 nM (ALKL1196)， 14-80 nM (ALKG1269A)， 38-50 nM (ALK1151Tins)， 77-113 nM (ALKG1202R)[3]Ki: WT)， 0.6 nM (ALKL1996M)， 0.9 nM (ALKG1269A)， 0.1 nM (ALK1151Tins)， L1152R)， 0.2 nM (ALKS1206Y)， C1156Y)， F1174L)[3] |
| In Vitro |
Lorlatinib (PF-06463922) 对 ALK 和大量 ALK 临床突变具有显著的细胞活性，IC50 范围为 0.2 nM-77 nM[1]。在携带 SLC34A2-ROS1 融合基因的 HCC78 人 NSCLC 细胞和表达人 CD74-ROS1 的 BaF3-CD74-ROS1 细胞中，Lorlatinib 显著抑制细胞增殖并诱导细胞凋亡。Lorlatinib 还显示出强大的生长抑制活性，并在携带非突变 ALK 或突变 ALK 融合的 NSCLC 细胞中诱导细胞凋亡[2]。 |
| In Vivo |
在大鼠中，Lorlatinib (PF-06463922) 表现出低血浆清除率、中等分布容积、合理的半衰期、低 p-糖蛋白 1 介导的外排倾向和 100% 的生物利用度[1]。在体内，Lorlatinib 通过抑制 ROS1 磷酸化和下游信号分子，以及抑制肿瘤中的细胞周期蛋白 Cyclin D1，在表达人 CD74-ROS1 和 Fig-ROS1 的 NIH3T3 异种移植模型中显示细胞减灭性抗肿瘤功效。Lorlatinib 还在携带表达 EML4-ALK、EML4-ALK-L1196M、EML4-ALK-G1269A、EML4-ALK-G1202R 或 NPM-ALK[2]的肿瘤异种移植物的小鼠中表现出显著的抗肿瘤活性。 |
| 细胞实验 |
Cells are seeded in 96-well plates in growth medium containing 10% FBS and are cultured overnight at 37°C. The following day， serial dilutions of Lorlatinib or appropriate controls are added to the designated wells， and cells are incubated at 37°C for 72 h. A CellTiter-Glo assay is performed to determine the relative cell numbers. IC50 values are calculated by concentration-response curve fitting using a four-parameter analytical method. |
| 动物实验 |
De novoGBM tumorigenesis is initiated in LSL-FIG-ROS1;Cdkn2a?/?;LSL-Luc mice through intracranial stereotactic injections of Adeno-Cre as described previously. Tumor development is monitored using BLI as described below. Once tumors reach a given size (107 p-1·s-1·cm-2·sr-1)， animals are randomLy enrolled into vehicle control or 3-， 7-， or 14-d treatment with the indicated doses of Lorlatinib. Drug is administered through s.c. implanted Alzet osmotic pumps. After treatment， mice are killed， GBM tumors are microdissected， and tissues are flash-frozen in liquid N2. The remaining brains are processed for histology. |
| 数据来源文献 |
[1]. Zou HY， et al. PF-06463922， an ALK/ROS1 Inhibitor， Overcomes Resistance to First and Second Generation ALK Inhibitors in Preclinical Models. Cancer Cell. 2015 Jul 13;28(1):70-81.
[2]. Johnson TW， et al. Discovery of (10R)-7-amino-12-fluoro-2，10，16-trimethyl-15-oxo-10，15，16，17-tetrahydro-2H-8，4-(metheno)pyrazolo[4，3-h][2，5，11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922)， a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations. J Med Chem. 2014 Jun 12;57(11):4720-44.
[3]. Zou HY， et al. PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking PF-02341066-resistant ROS1 mutations. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3493-8 |
| 规格 |
5mg 10mg 25mg 50mg 100mg |
| 单位 |
瓶 |
中文
英语
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