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Purity: ≥98%
Fenebrutinib (formerly RG-7845; GDC-0853) is a novel, potent, selective, orally bioavailable, and noncovalent (reversible) bruton's tyrosine kinase (BTK) inhibitor (Ki = 0.91 nM) with anticancer and anti-inflammatory activity. Treatment for systemic lupus erythematosus and rheumatoid arthritis is being developed. Administering GDC-0853 and other structurally diverse BTK inhibitors for at least seven days resulted in pancreatic lesions in Sprague-Dawley (SD) rats. These lesions included multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages, surrounded by lobular exocrine acinar cell atrophy, degeneration, and inflammation. At significantly higher exposures, no comparable results were seen in mice or dogs. Between four and seven daily doses of GDC-0853, peri-islet vasculature hemorrhage appeared. Histologically, this hemorrhage resembled changes that age-related SD rats naturally experience. This implies that GDC-0853 may make a background finding in juvenile animals worse. In the wake of a glucose challenge, there was dysregulation of glucose homeostasis; however, this was not linked to the onset or severity of pancreatic lesions and only happened after 28 days of administration. Other widely used blood biomarkers that evaluate exocrine and endocrine pancreatic function did not change. Neither magnetic resonance imaging nor computed tomography were able to easily identify these lesions. According to these findings, pancreatic lesions in rats are probably a class effect of BTK inhibitors, which could make an islet-centered pathology worse and make it less likely that humans will experience it. One of the cytoplasmic tyrosine kinases in the Tec family that is involved in B-cell and myeloid cell signaling is bruton's tyrosine kinase (BTK).
| Targets |
BTK (Ki = 0.91 nM); BTK C481R (Ki = 1.3 nM); BTK C481S (Ki = 1.6 nM); BTK T474M (Ki = 3.4 nM); BTK T474I (Ki = 12.6 nM)
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| ln Vitro |
GDC-0853 only inhibits 3 out of 286 off-target kinases in a broad panel of human kinase biochemical assays when tested at 1 μM. The selectivity for Btk is >100-fold against each of these three off-targets, according to the calculated IC50 values: Bmx (153-fold), Fgr (168-fold), and Src (131-fold). GDC-0853 inhibits the signaling of monocyte FcγR and B-cell BCR. The average residence time of GDC-0853 with Btk in the in vitro biochemical Btk enzyme assay is 18.3 ± 2.8 hours. GDC-0853 blocks cellular autophosphorylation of WT Btk and the C481S mutant[1]. GDC-0853 treatment of CLL (chronic lymphocytic leukemia) cells in vitro prior to BCR stimulation results in decreased BTK phosphorylation and decreased activation of downstream targets such as PLCγ2, AKT, and ERK. GDC-0853 decreases activation, hinders migration, and inhibits NF-κB-dependent transcription. GDC-0853 does not influence T-cell receptor activation and does not inhibit EGFR or ITK in the cellular system[3].
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| ln Vivo |
GDC-0853 has a moderate clearance of 27.4 mL/min/kg and an excellent bioavailability (F=65%) in rats administered 0.2 mg/kg via intraperitoneal injection or 1 mg/kg PO. The plasma half-life (t1/2) is 2.2 hours, the volume of distribution (Vd) is 5.42 L/kg, and the plasma clearance is 27.4 mL/min/kg. GDC-0853 shows positive PK characteristics in dogs as well. In canine toxicology research, achieving adequate exposures is further made possible by the 3.8-hour half-life (Clp 10.9 mL/min/kg, Vd 2.96 L/kg) and high oral bioavailability (85%). Both rats and dogs tolerate GDC-0853 well, and it has an overall good safety profile. GDC-0853 is helpful in the treatment of autoimmune diseases mediated by B-cells or myeloid cells, including rheumatoid arthritis. GDC-0853 has shown excellent tolerance in two studies: a single ascending dose (SAD) trial (0.5 mg to 600 mg) and a multiple ascending dose (MAD) study (250 mg BID to 500 mg QD) lasting 14 days. Both studies have shown no dose-limiting toxicities and no severe adverse events. GDC-0853 exhibits dose-proportional, linear pharmacokinetics and is well absorbed [1]. GDC-0853 and other structurally diverse BTK inhibitors administered for 7 days or more in Sprague-Dawley (SD) rats result in pancreatic lesions that include pigment-laden macrophages, inflammation, fibrosis, and multifocal islet-centered hemorrhage, along with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation. At far higher exposures, similar results are not seen in mice or dogs[2].
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| Enzyme Assay |
Btk inhibitor kinase selectivity is evaluated at a concentration of 1 µM in a panel of up to 287 recombinant human kinase activity and binding tests, such as lipid kinases, serine/threonine kinases, and cytoplasmic and receptor tyrosine kinases. Whereas the binding assays tracked the displacement of ATP sitebinding probes, the kinase activity assays quantify peptide phosphorylation or ADP production. For every kinase, the ATP concentrations used in the activity assays are usually within two times the experimentally determined apparent Michaelis constant (Kmapp) value, while the competitive binding tracer concentrations used in the binding assays are usually within three times the experimentally determined dissociation constant (Kd) values. For every kinase, inhibitors are tested in duplicate, and the mean percentage of inhibition is reported. The same assays are used for 10-point inhibitor titrations to identify the inhibitor concentrations that cause 50% inhibition (IC50) for kinases that are inhibited by nearly or more than 80% at the test concentration.
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| Cell Assay |
Cell viability is assessed using flow cytometry after a 48-hour treatment with a 1 µM BTK inhibitor.
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| Animal Protocol |
Sprague-Dawley, Wistar-Han and Fischer-344 rats (6 to 12 weeks old)
5 or 10 mL/kg p.o. |
| References |
| Molecular Formula |
C37H44N8O4
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| Molecular Weight |
664.7965
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| Exact Mass |
664.35
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| Elemental Analysis |
C, 66.85; H, 6.67; N, 16.86; O, 9.63
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| CAS # |
1434048-34-6
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| Related CAS # |
1434048-34-6;2128304-54-9 (HCl);2128304-53-8 (mesylate);2128304-55-0 (sulfate);
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| Appearance |
White to off-white solid powder
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| SMILES |
C[C@H]1CN(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
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| InChi Key |
WNEODWDFDXWOLU-QHCPKHFHSA-N
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| InChi Code |
InChI=1S/C37H44N8O4/c1-23-18-42(27-21-49-22-27)9-10-43(23)26-5-6-33(39-17-26)40-30-13-25(19-41(4)35(30)47)28-7-8-38-34(29(28)20-46)45-12-11-44-31(36(45)48)14-24-15-37(2,3)16-32(24)44/h5-8,13-14,17,19,23,27,46H,9-12,15-16,18,20-22H2,1-4H3,(H,39,40)/t23-/m0/s1
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| Chemical Name |
10-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-4,4-dimethyl-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-9-one
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| Synonyms |
RG-7845; GDC-0853; RG7845; GDC 0853; RG 7845; GDC0853
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ≥ 23 mg/mL (~34.6 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (1.50 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1 mg/mL (1.50 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1 mg/mL (1.50 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5042 mL | 7.5211 mL | 15.0421 mL | |
| 5 mM | 0.3008 mL | 1.5042 mL | 3.0084 mL | |
| 10 mM | 0.1504 mL | 0.7521 mL | 1.5042 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04544449 | Active Recruiting |
Drug: Fenebrutinib Drug: Ocrelizumab |
Multiple Sclerosis, Primary Progressive |
Hoffmann-La Roche | October 26, 2020 | Phase 3 |
| NCT05119569 | Active Recruiting |
Drug: Fenebrutinib Drug: Placebo |
Relapsing Multiple Sclerosis | Hoffmann-La Roche | March 1, 2022 | Phase 2 |
| NCT04586023 | Recruiting | Drug: Fenebrutinib Drug: Placebo |
Relapsing Multiple Sclerosis | Hoffmann-La Roche | March 24, 2021 | Phase 3 |
| NCT04586010 | Recruiting | Drug: Fenebrutinib Other: Placebo |
Relapsing Multiple Sclerosis | Hoffmann-La Roche | March 17, 2021 | Phase 3 |
| NCT03596632 | Completed | Drug: Fenebrutinib | Healthy Participants | Hoffmann-La Roche | July 27, 2018 | Phase 1 |
Representative photomicrographs of pancreatic histopathology observed in Sprague-Dawley rats following daily oral administration of GDC-0853 for 21 or 28 days are presented.J Pharmacol Exp Ther. 2017 Jan;360(1):226-238. |
Exposure to GDC-0853 in Sprague-Dawley rats relative to BTK (on-target) and off-target (BMX, FGR, SRC) kinase half-maximal inhibitory concentrations (IC50) is presented.
Strain sensitivity to BTK inhibitor–induced pancreatic lesions is presented.J Pharmacol Exp Ther. 2017 Jan;360(1):226-238. |
Relative Btk transcript expression (dCT; delta Cycle Threshold) in pancreatic tissue from humans and Sprague-Dawley rats is presented.
Glucose and insulin levels in Sprague-Dawley rats following administration of GDC-0853 are presented.J Pharmacol Exp Ther. 2017 Jan;360(1):226-238. |
Amylase, lipase, insulin, and fructosamine levels in Sprague-Dawley rats (n≤ 15 per sex per group) following administration of GDC-0853 are presented.J Pharmacol Exp Ther. 2017 Jan;360(1):226-238. |
Ultrasound imaging of the pancreas in Sprague-Dawley rats following administration of GNE-309 (n= 8 males per group) or GDC-0853 (n= 16 males per group) is presented.J Pharmacol Exp Ther. 2017 Jan;360(1):226-238. |
Molecular structures of BTK inhibitors GDC-0853, GNE-309, ibrutinib, and spebrutinib.J Pharmacol Exp Ther. 2017 Jan;360(1):226-238. |
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