| 名稱 | Lorlatinib |
| 描述 | Lorlatinib (PF-6463922) is an orally available, ATP-competitive inhibitor of the receptor tyrosine kinases, anaplastic lymphoma kinase (ALK) and C-ros oncogene 1 (Ros1), with potential antineoplastic activity. |
| 細(xì)胞實(shí)驗(yàn) | 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 PF-06463922 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. |
| 激酶實(shí)驗(yàn) | Recombinant human wild-type and mutant ALK kinase domain proteins (amino acids 1093–1411) are produced in-house using baculoviral expression, preactivated via autophosphorylation with MgATP, and assayed for kinase activity using a microfluidic mobility shift assay. The reactions contained 1.3 nM wild-type ALK or 0.5 nM mutant ALK (appropriate to produce 15-20% phosphorylation of peptide substrate after 1 h of reaction), 3 μM 5-FAM-KKSRGDYMTMQIG-CONH2), 5 mM MgCl2, and the Km level of ATP in 25 mM Hepes, pH 7.1. The inhibitors are shown to be ATP-competitive from kinetic and crystallographic studies. The Ki values are calculated by fitting the conversion (%) to a competitive inhibition equation. ROS1 enzyme is assayed as described above for ALK, except using 0.25 nM recombinant human ROS1 catalytic domain (amino acids 1883-2347). Kinase inhibitor selectivity is evaluated using a 206-kinase panel. |
| 體外活性 | 在含有SLC34A2-ROS1 融合物的HCC78人NSCLC細(xì)胞和表達(dá)人CD74-ROS1的BaF3-CD74-ROS1細(xì)胞中,PF-06463922能夠抑制細(xì)胞增殖,同時(shí)誘導(dǎo)細(xì)胞凋亡。在含有非突變型ALK或突變型ALK融合物的NSCLC 細(xì)胞中, PF-06463922能夠抑制細(xì)胞增殖,同時(shí)誘導(dǎo)細(xì)胞凋亡。對(duì)ALK和大量ALK臨床突變型（IC50=0.2 -77 nM）, PF-06463922表現(xiàn)出明顯的細(xì)胞活性。 |
| 體內(nèi)活性 | 在表達(dá)人CD74-ROS1 和 Fig-ROS1的NIH3T3異種移植模型中,PF-06463922通過抑制ROS1磷酸化和下游信號(hào)分子,以及對(duì)周期蛋白D1的抑制發(fā)揮作用,能夠抑制細(xì)胞增殖.在負(fù)荷腫瘤移植物,過表達(dá)EML4-ALK,EML4-ALK-L1196M,EML4-ALK-G1269A,EML4-ALK-G1202R 或NPM-ALK的小鼠體內(nèi),PF-06463922表現(xiàn)出明顯的抗腫瘤活性. |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | Ethanol : 40.6 mg/mL (100 mM)
DMSO : 15 mg/mL (36.91 mM), Sonication is recommended.
|
| 關(guān)鍵字 | ALK tyrosine kinase receptor | Anaplastic lymphoma kinase | PF 06463922 | tyrosine | Apoptosis | inhibit | Neuroblastoma | Carcinoma | Anaplastic lymphoma kinase (ALK) | Lorlatinib | NSCLC | Inhibitor | PF06463922 | mutation | PF 6463922 | kinase | Cluster of differentiation 246 | brain-penetrant | ROS Kinase | CD246 | third-generation | PF6463922 |
| 相關(guān)產(chǎn)品 | L-Glutamic acid | Gefitinib | Metronidazole | 5-Fluorouracil | Dextran sulfate sodium salt (MW 4500-5500) | Stavudine | Tributyrin | Myricetin | L-Ascorbic acid | Acetylcysteine | Salicylic acid | Sodium 4-phenylbutyrate |
| 相關(guān)庫(kù) | 抑制劑庫(kù) | 經(jīng)典已知活性庫(kù) | 已知活性化合物庫(kù) | 激酶抑制劑庫(kù) | EMA 上市藥物庫(kù) | 膜蛋白靶向化合物庫(kù) | 藥物功能重定位化合物庫(kù) | 酪氨酸激酶分子庫(kù) | FDA 上市激酶抑制劑庫(kù) | 抗癌臨床化合物庫(kù) |