受注:045-509-1970 |
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Synonyms | N/A | Storage (From the date of receipt) |
3 years -20°C powder | ||||||||
化学式 | C37H44N8O4 |
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分子量 | 664.80 | CAS No. | 1434048-34-6 | ||||||||
Solubility (25°C)* | 体外 | DMSO | 8 mg/mL (12.03 mM) | ||||||||
Water | Insoluble | ||||||||||
Ethanol | 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 | Fenebrutinib (GDC-0853) is a potent, selective, and non-covalent bruton's tyrosine kinase (BTK) inhibitor with an Ki value of 0.91 nM for Btk with >100-fold selectivity over 3 off-targets (Bmx :153-fold, Fgr: 168-fold, Src:131-fold). |
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in vitro | When tested at 1 μM against a broad panel of human kinase biochemical assays, GDC-0853 inhibits only 3 of 286 off-target kinases. Based on the determined IC50 values, the selectivity for Btk is >100-fold against each of these 3 off-targets: Bmx (153-fold), Fgr (168-fold), and Src (131-fold). GDC-0853 blocks both B-cell BCR and monocyte FcγR signaling. In in vitro biochemical Btk enzyme assay, GDC-0853 displays an average residence time with Btk of 18.3 ± 2.8 hours. GDC-0853 blocks cellular autophosphorylation of WT Btk and the C481S mutant[1]. CLL (chronic lymphocytic leukemia) cells treated with GDC-0853 in vitro before BCR stimulation demonstrate reduced levels of BTK phosphorylation and diminished activation of downstream targets including PLCγ2, AKT, and ERK. GDC-0853 inhibits NF-κB–dependent transcription, reduces activation, and impairs migration. GDC-0853 lacks inhibition of EGFR and ITK in cellular system and does not affect T-cell receptor activation[3]. |
in vivo | In rats administrated 0.2 mg/kg GDC-0853 via intraperitoneal injection or 1 mg/kg PO, GDC-0853 has moderate clearance of 27.4 mL/min/kg and excellent bioavailability (F=65%). The plasma clearance is 27.4 mL/min/kg, the volume of distribution (Vd) is 5.42 L/kg and the plasma half-life (t1/2) is 2.2 h. GDC-0853 also demonstrates favorable PK properties in dogs. The 3.8-hour half-life (Clp 10.9 mL/min/kg, Vd 2.96 L/kg) and high oral bioavailability (85%) also enable attainment of sufficient exposures in dog toxicology studies. GDC-0853 is well tolerated in both rats and dogs and displays an overall favorable safety profile. GDC-0853 is useful in treating rheumatoid arthritis and other B-cell or myeloid cell mediated autoimmune diseases. In a single ascending dose (SAD) study (0.5 mg to 600 mg) and multiple ascending dose (MAD) study for 14 days (250 mg BID to 500 mg QD), GDC-0853 is very well tolerated with no severe adverse events, no safety signals, and no dose limiting toxicities. GDC-0853 is well absorbed and had linear, doseproportional pharmacokinetics[1]. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer cause pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation. Similar findings are not observed in mice or dogs at much higher exposures[2]. |
キナーゼアッセイ | Kinase selectivity | |
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Btk inhibitor kinase selectivity is assessed at a concentration of 1 µM in a panel of up to 287 recombinant human kinase activity and binding assays, including cytoplasmic and receptor tyrosine kinases, serine/threonine kinases, and lipid kinases. The kinase activity assays measure peptide phosphorylation or ADP production while the binding assays monitored displacement of ATP sitebinding probes. The ATP concentrations used in the activity assays are typically within 2-fold of the experimentally determined apparent Michaelis constant (Kmapp) value for each kinase while the competitive binding tracer concentrations used in the binding assays are generally within 3-fold of the experimentally determined dissociation constant (Kd) values. Inhibitors are tested in duplicate against each kinase and the mean % Inhibition values are reported. For kinases that are inhibited by close to or greater than 80% at the test concentration, 10-point inhibitor titrations using the same assays are carried out in order to determine the inhibitor concentrations that caused 50% inhibition (IC50). | ||
細胞アッセイ | 細胞株 | CLL cells |
濃度 | 1 μM | |
反応時間 | 48 hours | |
実験の流れ | Cells are treated with 1 µM BTK inhibitor for 48 hours and measured for viability by flow cytometry. |
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動物実験 | 動物モデル | Sprague-Dawley, Wistar-Han and Fischer-344 rats (6 to 12 weeks old) |
投薬量 | 5 or 10 mL/kg | |
投与方法 | p.o. |
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Assessment of the effects of Syk and BTK inhibitors on GPVI-mediated platelet signaling and function [ Am J Physiol Cell Physiol, 2021, 320(5):C902-C915] | PubMed: 33689480 |
CD81 knockout promotes chemosensitivity and disrupts in vivo homing and engraftment in acute lymphoblastic leukemia [ Blood Adv, 2020, 4(18):4393-4405] | PubMed: 32926125 |
Effects of Inhibitors against Syk-BTK-PI3K Signaling on Platelet Function [ ScholarsArchive@OSU, 2020, 51] | PubMed: N/A |
Effects of Inhibitors against Syk-BTK-PI3K Signaling on Platelet Function [ ScholarsArchive@OSU, 2020, None] | PubMed: None |
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。