| Name | Lorlatinib |
| Description | 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. |
| Cell Research | 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. |
| Kinase Assay | 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. |
| In vitro | PF-06463922 effectively inhibits cell proliferation and induces apoptosis in HCC78 human NSCLC cells containing SLC34A2-ROS1 fusions and in BaF3-CD74-ROS1 cells expressing human CD74-ROS1. It also demonstrates this inhibitory action on cell proliferation and induces apoptosis in NSCLC cells with either non-mutated or mutated ALK fusions. PF-06463922 exhibits significant cellular activity against ALK and a wide range of ALK clinical mutations (IC50=0.2-77 nM). |
| In vivo | In NIH3T3 xenograft models expressing human CD74-ROS1 and Fig-ROS1, PF-06463922 inhibits cell proliferation by repressing ROS1 phosphorylation and downstream signaling molecules, including Cyclin D1. Furthermore, PF-06463922 demonstrates significant antitumor activity in mice bearing tumor grafts that overexpress EML4-ALK, EML4-ALK-L1196M, EML4-ALK-G1269A, EML4-ALK-G1202R, or NPM-ALK. |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| Solubility Information | Ethanol : 40.6 mg/mL (100 mM)
DMSO : 15 mg/mL (36.91 mM), Sonication is recommended.
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| Keywords | 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 |
| Inhibitors Related | Stavudine | 5-Fluorouracil | Myricetin | Sodium 4-phenylbutyrate | L-Ascorbic acid | Dextran sulfate sodium salt (MW 4500-5500) | Metronidazole | Sorafenib | Tributyrin | Gefitinib |
| Related Compound Libraries | Membrane Protein-targeted Compound Library | EMA Approved Drug Library | Tyrosine Kinase Inhibitor Library | Kinase Inhibitor Library | Inhibitor Library | Anti-Cancer Approved Drug Library | FDA-Approved Drug Library | Anti-Aging Compound Library | Bioactive Compounds Library Max | Anti-Cancer Drug Library |
United States
