Fenebrutinib (GDC-0853)

Catalog No.S8421

Fenebrutinib (GDC-0853) Chemical Structure

Molecular Weight(MW): 664.80

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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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].

Assay
Methods Test Index PMID
Western blot
p-BTK / BTK / p-PLCγ2 / PLCγ2 / p-AKT / AKT / p-ERK / ERK ; 

PubMed: 30018078     


Representative immunoblot demonstrating the effect of GDC-0853 on BCR signaling. 

30018078
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

Kinase Assay:

[1]

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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 Research:

[3]

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  • 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.


    (Only for Reference)
Animal Research:

[2]

+ Expand
  • Animal Models: Sprague-Dawley, Wistar-Han and Fischer-344 rats (6 to 12 weeks old)
  • Formulation: 1.0% (w/v) 4000 cps hydroxypropylmethylcellulose, 0.2% (v/v) Tween 80 and 100 mM citrate buffer (pH 3.0 ± 0.1) prepared in reverse osmosis water
  • Dosages: 5 or 10 mL/kg
  • Administration: p.o.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 8 mg/mL (12.03 mM)
Water Insoluble
Ethanol 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.

Chemical Information

Molecular Weight 664.80
Formula

C37H44N8O4

CAS No. 1434048-34-6
Storage powder
in solvent
Synonyms N/A

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03693625 Recruiting Drug: Fenebrutinib Urticaria Genentech Inc. September 27 2018 Phase 2
NCT03596632 Completed Drug: Fenebrutinib Healthy Participants Hoffmann-La Roche July 27 2018 Phase 1
NCT03407482 Active not recruiting Drug: GDC-0853 Lupus Erythematosus Systemic Genentech Inc. January 9 2018 Phase 2
NCT03137069 Recruiting Drug: GDC-0853|Drug: Placebo Urticaria Genentech Inc. May 26 2017 Phase 2
NCT03290703 Completed Drug: GDC-0853|Drug: Rabeprazole Healthy Volunteers Genentech Inc. April 18 2017 Phase 1
NCT03188783 Completed Drug: GDC-0853|Drug: Placebo Healthy Volunteer Hoffmann-La Roche January 24 2017 Phase 1

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Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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BTK Signaling Pathway Map

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID