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| 25mg |
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Purity: ≥98%
Tirabrutinib HCl (formerly known as ONO-4059; GS4059; ONO-WG-307; Steboronine), the hydrochloride salt of tirabrutinib, is a selective, covalent/irreversible and orally bioavailable BTK inhibitor approved in Japan for cancer treatment. It inhibits BTK with an IC50 of 2.2 nM. Tirabrutinib covalently binds to BTK within B cells, thereby preventing B-cell receptor signaling and impeding B-cell development. As a result, this agent may inhibit the proliferation of B-cell malignancies. BTK, a cytoplasmic tyrosine kinase and member of the Tec family of kinases, plays an important role in B lymphocyte development, activation, signaling, proliferation and survival.
| ln Vitro |
OCI-L Y10 and SU-DHL-6 cell growth is inhibited by tirabrutinib hydrochloride (0.1-1000 nM or 0.001-100 nM; 72 h), with IC50 values of 9.127 nM and 17.10 nM, respectively [1]. Tibrutinib hydrochloride (0.5, 5, 50 μM; 24, 48 h) causes SU-DHL-6 cells to undergo apoptosis; this requires large doses and prolonged administration (48 h of incubation at concentrations up to 50 μM) [1]. In TMD8 cells, tirabotinib hydrochloride (300 nM, 72 hours) causes caspase-3 and PARP cleavage [2].
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| ln Vivo |
The oral single-dose dose of tiprunitinib hydrochloride (10 mg/kg) is rapidly absorbed into the brain and plasma, reaching its maximum concentration two hours after administration (blood Cmax = 339.53 ng/mL, brain Cmax = 28.9 ng/mL) [1]. In vivo, tibrutinib hydrochloride (6, 20 mg/kg; oral; once daily for 3 weeks) has demonstrated growth-inhibiting properties for tumors [2].
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| Cell Assay |
Cell proliferation assay [1]
Cell Types: SU-DHL-6 and OCI-LY Y10 Cell Tested Concentrations: 0.1-1000 nM; 0.001nM-100nM. Incubation Duration: 72 hrs (hours) Experimental Results: demonstrated good anti-proliferative activity with IC50 of 9.127 nM and 17.10 nM for OCI-L Y10 and SU-DHL-6 cells respectively. Cell apoptosis analysis [1] Cell Types: SU-DHL-6 Cell Tested Concentrations: 0.5, 5, 50 μM Incubation Duration: 24, 48 h Experimental Results: Cell apoptosis was induced when the concentration reached 50 μM and incubated for 48 h. Western Blot Analysis[2] Cell Types: TMD8 Cell Tested Concentrations: 300 nM Incubation Duration: 72 hrs (hours) Experimental Results: Induction of caspase-3 and PARP cleavage. |
| Animal Protocol |
Animal/Disease Models: Male SD rat (219.0–260.5g) [1].
Doses: 10 mg/kg Route of Administration: Oral; single. Experimental Results: 1.19 pharmacokinetic/PK/PK parameters of tilatinib in male SD rats [1]. Plasma, Cmax (ng/mL) Brain, Cmax (ng/mL) Permeability (%, Cmax, brain/Cmax, plasma) PO (10 mg/kg) 339.53 28.9 8.5 Animal/Disease Models: Immunodeficient (SCID) mice ( Mouse xenograft model) [2]. Doses: 6, 20 mg/kg Route of Administration: po (po (oral gavage)) one time/day for 3 weeks. Experimental Results: Inhibited tumor growth. When the dose reached 20 mg/kg, the tumor was completely inhibited on the 14th day. |
| References |
[1]. Yu H, et al. Bruton's tyrosine kinase inhibitors in primary central nervous system lymphoma-evaluation of anti-tumor efficacy and brain distribution. Transl Cancer Res. 2021 May;10(5):1975-1983.
[2]. Kozaki R, et al. Responses to the Selective Bruton's Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines. Cancers (Basel). 2018 Apr 23;10(4):127. [3]. Liclican A, et al. Biochemical characterization of tirabrutinib and other irreversible inhibitors of Bruton's tyrosine kinase reveals differences in on - and off - target inhibition. Biochim Biophys Acta Gen Subj. 2020 Apr;1864(4):129531. [4]. Dhillon S. Tirabrutinib: First Approval. Drugs. 2020 Jun;80(8):835-840. |
| Molecular Formula |
C25H23CLN6O3
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|---|---|
| Molecular Weight |
490.948
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| CAS # |
1439901-97-9
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| Related CAS # |
Tirabrutinib;1351636-18-4;ONO-4059 analog;1351635-67-0
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| SMILES |
O=C(N1C[C@@H](CC1)N(C2=O)C3=NC=NC(N)=C3N2C4=CC=C(C=C4)OC5=CC=CC=C5)C#CC.[H]Cl
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| InChi Key |
UQYDCIJFACDXSG-GMUIIQOCSA-N
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| InChi Code |
InChI=1S/C25H22N6O3.ClH/c1-2-6-21(32)29-14-13-18(15-29)31-24-22(23(26)27-16-28-24)30(25(31)33)17-9-11-20(12-10-17)34-19-7-4-3-5-8-19/h3-5,7-12,16,18H,13-15H2,1H3,(H2,26,27,28)1H/t18-/m1./s1
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| Chemical Name |
(R)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one hydrochloride
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| Synonyms |
GS4059 ONO-WG-307ONO-4059 HCl GS 4059ONO4059 ONO 4059 ONO-4059 GS-4059 Tirabrutinib
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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 (~203.69 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.09 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.09 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. View More
Solubility in Formulation 3: ≥ 1.79 mg/mL (3.65 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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0369 mL | 10.1843 mL | 20.3687 mL | |
| 5 mM | 0.4074 mL | 2.0369 mL | 4.0737 mL | |
| 10 mM | 0.2037 mL | 1.0184 mL | 2.0369 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.
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