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| Targets |
Atuzabrutinib targets Bruton's tyrosine kinase (Btk), a non-receptor tyrosine kinase that is essential for B-cell receptor signaling and the activation of various immune cells. It is a reversible and selective Btk inhibitor. By inhibiting Btk, Atuzabrutinib modulates immune responses, which is beneficial in autoimmune and inflammatory conditions. It exhibits durable but reversible occupancy with rapid on-rate and slow off-rate binding kinetics. The compound binds to the ATP-binding pocket of Btk, inhibiting its kinase activity and downstream signaling pathways. Its selectivity for Btk over other kinases is a key feature of its pharmacological profile.
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| ln Vitro |
Atuzabrutinib demonstrates potent in vitro activity as a selective Btk inhibitor. It effectively prevents neutrophil recruitment by inhibiting macrophage antigen-1 signaling. The compound's rapid on-rate and slow off-rate binding kinetics translate into a rapid and long duration of action in vitro. In cell-based assays, Atuzabrutinib inhibits Btk phosphorylation and downstream signaling events in B cells and other immune cells. Its ability to modulate immune cell function makes it a valuable tool for studying the role of Btk in autoimmune diseases.
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| ln Vivo |
In a model of sterile liver injury, PRN473 (20 mg/kg) greatly lowers intravascular crawling and neutrophil recruitment into inflamed tissue, down to levels observed in animals lacking Btk[1].
Atuzabrutinib has been evaluated in in vivo models of autoimmune diseases. In a model of sterile liver injury, PRN473 (20 mg/kg) greatly lowers intravascular crawling and neutrophil recruitment into inflamed tissue, down to levels observed in animals lacking Btk. It has also been studied in a Phase 2a trial for mild-to-moderate atopic dermatitis. In phase 2 clinical trials in patients, it has demonstrated potential for treating autoimmune conditions. The compound's oral bioavailability and favorable pharmacokinetic profile support its development for autoimmune indications. |
| Enzyme Assay |
The in vitro enzyme/receptor binding (non-cell-based) assay for Atuzabrutinib involves assessing its binding affinity and inhibitory activity against BTK. Surface plasmon resonance (SPR) is used to measure the binding kinetics, demonstrating rapid on-rate and slow off-rate binding to BTK. Kinase assays are performed using recombinant BTK to determine the IC50 value for inhibition of BTK activity. The compound's selectivity over other kinases is confirmed through profiling against a panel of kinases. The binding affinity (Kd) and inhibition constant (Ki) are determined from these assays.
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| Cell Assay |
The in vitro cell-based assay for Atuzabrutinib involves treating immune cells, such as macrophages or B cells, with the compound and measuring BTK-dependent signaling and functional responses. The inhibition of neutrophil recruitment is assessed by measuring the inhibition of macrophage antigen-1 signaling. BTK phosphorylation and downstream signaling events are measured by Western blotting or flow cytometry. B-cell receptor (BCR)-induced calcium flux and proliferation are also measured to assess the functional consequences of BTK inhibition. The compound's ability to modulate cytokine production is evaluated in stimulated immune cells.
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| Animal Protocol |
In vivo animal experiments for Atuzabrutinib are conducted in models of autoimmune and inflammatory diseases. In a sterile liver injury model, animals are administered PRN473 (20 mg/kg), and the effects on intravascular crawling and neutrophil recruitment are measured. In models of rheumatoid arthritis and pemphigus vulgaris, the compound's ability to reduce disease severity is assessed. Pharmacodynamic markers, such as BTK phosphorylation in immune cells, are measured to confirm target engagement. The compound's oral bioavailability and efficacy are evaluated in these models.
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| ADME/Pharmacokinetics |
Atuzabrutinib is an orally bioavailable compound. It has a molecular weight of 539.60 g/mol and a molecular formula of C30H30FN7O2. It is soluble in DMSO at 80 mg/mL and has a LogP of 5.1. In vivo formulation can be prepared using 10% DMSO + 90% Corn Oil. The compound is typically stored as a powder at -20°C for up to 3 years. Its physicochemical properties support oral administration and favorable absorption.
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| Toxicity/Toxicokinetics |
As a research compound, its safety profile is evaluated in standard cytotoxicity and acute toxicity assays. The compound is classified for research use only and is not intended for human therapeutic use. Comprehensive toxicological characterization would be required prior to any clinical development. The compound is typically handled with standard laboratory safety precautions.
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| References | |
| Additional Infomation |
Atuzabrutinib (SAR 444727; PRN473, CAS 1581714-49-9) is a potent, selective, and reversible BTK inhibitor. It has a molecular weight of 539.60 and a molecular formula of C30H30FN7O2. It is also known as SAR 444727 and PRN473. The compound has been investigated in Phase 2 clinical trials for autoimmune diseases. It is not approved for clinical use and is available only for research purposes. The compound's mechanism of action involves reversible inhibition of BTK, modulating immune responses in autoimmune and inflammatory conditions.
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| Molecular Formula |
C30H30FN7O2
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| Molecular Weight |
539.603309154511
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| Exact Mass |
539.244
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| CAS # |
1581714-49-9
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| PubChem CID |
73438222
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| Appearance |
White to off-white solid powder
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| LogP |
5.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
40
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| Complexity |
971
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| Defined Atom Stereocenter Count |
1
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| SMILES |
NC1N=CN=C2N([C@@H]3CCCN(C(=O)/C(/C#N)=C/C(C)(C)C)C3)N=C(C3C=CC(OC4C=CC=CC=4)=CC=3F)C=12
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| InChi Key |
KZMQPYCXSAGLTB-ZWUNQBBJSA-N
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| InChi Code |
InChI=1S/C30H30FN7O2/c1-30(2,3)15-19(16-32)29(39)37-13-7-8-20(17-37)38-28-25(27(33)34-18-35-28)26(36-38)23-12-11-22(14-24(23)31)40-21-9-5-4-6-10-21/h4-6,9-12,14-15,18,20H,7-8,13,17H2,1-3H3,(H2,33,34,35)/b19-15+/t20-/m1/s1
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| Chemical Name |
(E)-2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4,4-dimethylpent-2-enenitrile
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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 |
| 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: 100 mg/mL (185.32 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.63 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8532 mL | 9.2661 mL | 18.5322 mL | |
| 5 mM | 0.3706 mL | 1.8532 mL | 3.7064 mL | |
| 10 mM | 0.1853 mL | 0.9266 mL | 1.8532 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.
Link: https://clinicaltrials.gov/ct2/show/NCT04992546
Conditions:Atopic DermatitisProducts are for research use only; We do not sell to patients
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