受注:045-509-1970 |
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Synonyms | N/A | Storage (From the date of receipt) |
3 years -20°C powder 1 years -80°C in solvent |
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化学式 | C21H19FN6O2 |
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分子量 | 406.41 | CAS No. | 1454846-35-5 | ||||||||
Solubility (25°C)* | 体外 | DMSO (warmed with 50ºC water bath) | 81 mg/mL (199.3 mM) | ||||||||
Ethanol (warmed with 50ºC water bath) | 81 mg/mL (199.3 mM) | ||||||||||
Water | Insoluble | ||||||||||
体内 (毎回新しく調製した物を用意してください) |
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* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. |
製品説明 | Lorlatinib (PF-6463922) is a potent, dual ALK/ROS1 inhibitor with Ki of <0.02 nM, <0.07 nM, and 0.7 nM for ROS1, ALK (WT), and ALK (L1196M), respectively. PF-06463922 induces apoptosis. Phase 1. |
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in vitro | PF-06463922 demonstrates significant cell activity against ALK and a large set of ALK clinical mutations with IC50 ranging from 0.2 nM-77 nM. [1] PF-06463922 significantly inhibits cell proliferation and induces cell apoptosis in the HCC78 human NSCLC cells harboring SLC34A2-ROS1 fusions and the BaF3-CD74-ROS1 cells expressing human CD74-ROS1.[2] PF-06463922 also shows potent growth inhibitory activity and induces apoptosis in the NSCLC cells harboring either non-mutant ALK or mutant ALK fusions. [3] |
in vivo | In rats, PF-06463922 displays low plasma clearance, a moderate volume of distribution, a reasonable half-life, low propensity for p-glycoprotein 1-mediated efflux and a bioavailability of 100%. [1] In vivo, PF-06463922 shows cytoreductive antitumor efficacy in the NIH3T3 xenograft models expressing human CD74-ROS1 and Fig-ROS1 via inhibition in ROS1 phosphorylation and the downstream signaling molecules, as well as inhibition of the cell cycle protein Cyclin D1 in tumors. [2] In vivo, PF-06463922 also demonstrates marked antitumor activity in mice bearing tumor xenografts expressing EML4-ALK, EML4-ALK-L1196M, EML4-ALK-G1269A, EML4-ALK-G1202R or NPM-ALK. [3] |
キナーゼアッセイ | Biochemical Kinase Assays | |
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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. |
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Data from [Data independently produced by , , Oncotarget, 2016, DOI: 10.18632/oncotarget.13541.]
Data from [Data independently produced by , , Mol Cancer Res, 2018, 10.1158/1541-7786.MCR-18-0171]
Data from [Data independently produced by , , Int J Oncol, 2017, 51(5):1533-1540]
NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance Mutations [ Cancer Discov, 2023, 13(3):598-615] | PubMed: 36511802 |
Circulating tumor DNA reveals mechanisms of lorlatinib resistance in patients with relapsed/refractory ALK-driven neuroblastoma [ Nat Commun, 2023, 14(1):2601] | PubMed: 37147298 |
Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models [ Clin Cancer Res, 2023, 29(7):1317-1331] | PubMed: 36602782 |
Discovery of oncogenic ROS1 missense mutations with sensitivity to tyrosine kinase inhibitors [ EMBO Mol Med, 2023, 10.15252/emmm.202217367] | PubMed: 37587872 |
Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer [ NPJ Precis Oncol, 2023, 7(1):12] | PubMed: 36702855 |
FGFR blockade inhibits targeted therapy-tolerant persister in basal FGFR1- and FGF2-high cancers with driver oncogenes [ NPJ Precis Oncol, 2023, 7(1):107] | PubMed: 37880373 |
FGFR blockade inhibits targeted therapy-tolerant persister in basal FGFR1- and FGF2-high cancers with driver oncogenes [ NPJ Precis Oncol, 2023, 7(1):107] | PubMed: 37880373 |
Pan-HER inhibitors overcome lorlatinib resistance caused by NRG1/HER3 activation in ALK-rearranged lung cancer [ Cancer Sci, 2023, 10.1111/cas.15579] | PubMed: 36086904 |
Pan-HER inhibitors overcome lorlatinib resistance caused by NRG1/HER3 activation in ALK-rearranged lung cancer [ Cancer Sci, 2023, 114(1):164-173] | PubMed: 36086904 |
Tyrosine Kinase Inhibitors Target B Lymphocytes [ Biomolecules, 2023, 13(3)438] | PubMed: 36979373 |
長期の保管のために-20°Cの下で製品を保ってください。
人間や獣医の診断であるか治療的な使用のためにでない。
各々の製品のための特定の保管と取扱い情報は、製品データシートの上で示されます。大部分のSelleck製品は、推薦された状況の下で安定です。製品は、推薦された保管温度と異なる温度で、時々出荷されます。長期の保管のために必要とされてそれと異なる温度で、多くの製品は、短期もので安定です。品質を維持するが、夜通しの積荷のために最も経済的な貯蔵状況を用いてあなたの送料を保存する状況の下に、製品が出荷されることを、我々は確実とします。製品の受領と同時に、製品データシートの上で貯蔵推薦に従ってください。