Fenebrutinib (GDC-0853)

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).

Fenebrutinib (GDC-0853)化学構造

CAS No. 1434048-34-6

サイズ 価格(税別) 在庫状況
JPY 22000 国内在庫あり
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JPY 295500 国内在庫なし(納期7~10日)

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文献中Selleckの製品使用例(4)

製品安全説明書

現在のバッチを見る: S842101 DMSO] 8 mg/mL] false] Water] Insoluble] false] Ethanol] Insoluble] false 純度: 99.91%
99.91

Fenebrutinib (GDC-0853)関連製品

シグナル伝達経路

BTK阻害剤の選択性比較

生物活性

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).
Targets
BTK [1]
(Cell-free assay)
BTK C481R [1]
(Cell-free assay)
BTK C481S [1]
(Cell-free assay)
BTK T474M [1]
(Cell-free assay)
BTK T474I [1]
(Cell-free assay)
0.91 nM(Ki) 1.3 nM(Ki) 1.6 nM(Ki) 3.4 nM(Ki) 12.6 nM(Ki)
In Vitro
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].

Kinase Assay Kinase selectivity
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).
細胞実験 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.

実験結果図 Methods Biomarkers 結果図 PMID
Western blot p-BTK / BTK / p-PLCγ2 / PLCγ2 / p-AKT / AKT / p-ERK / ERK 30018078
In Vivo
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].

動物実験 動物モデル Sprague-Dawley, Wistar-Han and Fischer-344 rats (6 to 12 weeks old)
投与量 5 or 10 mL/kg
投与経路 p.o.
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT05119569 Active not recruiting
Relapsing Multiple Sclerosis
Hoffmann-La Roche
March 1 2022 Phase 2
NCT04586023 Active not recruiting
Relapsing Multiple Sclerosis
Hoffmann-La Roche
March 24 2021 Phase 3
NCT04586010 Active not recruiting
Relapsing Multiple Sclerosis
Hoffmann-La Roche
March 17 2021 Phase 3
NCT03693625 Terminated
Urticaria
Genentech Inc.
September 27 2018 Phase 2
NCT03596632 Completed
Healthy Participants
Hoffmann-La Roche
July 27 2018 Phase 1

化学情報

分子量 664.80 化学式

C37H44N8O4

CAS No. 1434048-34-6 SDF --
Smiles CC1CN(CCN1C2=CN=C(C=C2)NC3=CC(=CN(C3=O)C)C4=C(C(=NC=C4)N5CCN6C7=C(CC(C7)(C)C)C=C6C5=O)CO)C8COC8
保管 3 years -20°C powder

In vitro
Batch:

DMSO : 8 mg/mL ( (12.03 mM); 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Water : Insoluble

Ethanol : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ1:実験データを入力してください。(実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します)

mg/kg g μL

ステップ2:投与溶媒の組成を入力してください。(ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください)

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果:

投与溶媒濃度: mg/ml;

DMSOストック溶液調製方法: mg 試薬を μL DMSOに溶解する(濃度 mg/mL, 注:濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法:Take μL DMSOストック溶液に μL PEG300,を加え、完全溶解後μL Tween 80,を加えて完全溶解させた後 μL ddH2O,を加え完全に溶解させます。

投与溶媒調製方法:μL DMSOストック溶液に μL Corn oil,を加え、完全溶解。

注意:1.ストック溶液に沈殿、混濁などがないことをご確認ください;
2.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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