Fenebrutinib (GDC-0853)

Catalog No.S8421 Batch:S842101

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Technical Data

Formula

C37H44N8O4

Molecular Weight 664.80 CAS No. 1434048-34-6
Solubility (25°C)* In vitro DMSO 8 mg/mL (12.03 mM)
Water Insoluble
Ethanol Insoluble
In vivo (Add solvents to the product individually and in order)
Clear solution
5% DMSO 95% Corn oil
0.2mg/ml Taking the 1 mL working solution as an example, add 50 μL of 4 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results. 
Clear solution
5%DMSO 40%PEG300 5%Tween80 50%ddH2O
0.4mg/ml Taking the 1 mL working solution as an example, add 50 μL of 8 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to clarify; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results. 
* <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.
* Room temperature shipping (Stability testing shows this product can be shipped without any cooling measures.)

Preparing Stock Solutions

Biological Activity

Description 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

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].

Protocol (from reference)

Kinase Assay:

[1]

  • 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).

Cell Assay:

[3]

  • Cell lines

    CLL cells

  • Concentrations

    1 μM

  • Incubation Time

    48 hours

  • Method

    Cells are treated with 1 µM BTK inhibitor for 48 hours and measured for viability by flow cytometry.

Animal Study:

[2]

  • Animal Models

    Sprague-Dawley, Wistar-Han and Fischer-344 rats (6 to 12 weeks old)

  • Dosages

    5 or 10 mL/kg

  • Administration

    p.o.

Selleck's Fenebrutinib (GDC-0853) has been cited by 4 publications

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

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SHIPPING AND STORAGE
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