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Purity: ≥98%
ONO-4059 analogue, an analogue of ONO-4059, is a novel, covalent, selective and orally bioavailable BTK inhibitor with potential anticancer and anti-inflammatory activity. It inhibits BTK with IC50 of 23.9 nM. ONO-4059 has demonstrated high antitumor activity in several pre-clinical models. It potently and dose-dependently reverse clinical arthritis and prevented bone damage in the CIA model. ONO-4059 inhibited the TMD-8 cell growth and Btk phosphorylation in a concentration-dependent manner. Furthermore, the decrease in Btk phosphorylation subsequently down-regulated Erk phosphorylation. After the combination of ONO-4059 with doxorubicin, etoposide, vincristine and dexamethasone, increased apoptosis ratio was observed, 25, 20, 17 and 29%, respectively.
| Targets |
BTK
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| ln Vitro |
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| ln Vivo |
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| Enzyme Assay |
Determination of covalent binding. [Biochim Biophys Acta Gen Subj. 2020 Apr;1864(4):129531.]
Protein labeling experiments were performed using BTK at a final concentration of 2 μM in a buffer solution containing 10 mM HEPES, pH 7.5, 150 mM sodium chloride, 10 mM magnesium chloride, 2 mM Tris(2-carboxyethyl)phosphine (TCEP), and 1% glycerol. Inhibitors were added to a final concentration of 10 μM, with a final concentration of 1% DMSO in all samples. Four conditions were tested, each run in triplicate: BTK + tirabrutinib, BTK + staurosporine, BTK + ibrutinib, and BTK + DMSO control. After compound addition, samples were incubated overnight at 4 °C in a rotating shaker (1200 rpm). After an 18-h incubation, aliquots were collected from each condition for analysis and this time point was termed t = pre-chase. A chase step was then performed with the remaining sample by addition of ibrutinib into the BTK + tirabrutinib and BTK + staurosporine samples to a final concentration of 100 μM. An equivalent amount of DMSO was added to the BTK + ibrutinib and BTK + DMSO control samples to maintain the same volume. After incubating for 6 h at 4 °C, the remaining sample was collected at the final time point, termed t = post-chase. Aliquots taken at both time points were analyzed at the time of collection using mass spectrometry and enzyme activity assays. Mass spectrometry analysis was performed on an Agilent 6210 Time of Flight Mass Spectrometer with an Agilent 1200 Rapid Resolution HPLC using Masshunter B.05 Acquisition software. Samples were run on an Agilent Zorbax 300 Extend C18 rapid resolution column at 70 °C, using reverse phase chromatography with a gradient from 20% to 90% acetonitrile containing 0.1% formic acid. Data were processed using Agilent MassHunter Qualitative Analysis B.06, with a BioConfirm workflow allowing for protein deconvolution to obtain neutral mass values. |
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| References |
Blood.2016Jan 28;127(4):411-9.
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| Additional Infomation |
See also: Tirabrutinib (annotation moved to).
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| Molecular Formula |
C25H24N6O3
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| Molecular Weight |
456.50
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| Exact Mass |
456.19
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| Elemental Analysis |
C, 65.78; H, 5.30; N, 18.41; O, 10.51
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| CAS # |
1351635-67-0
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| Related CAS # |
Tirabrutinib;1351636-18-4;Tirabrutinib hydrochloride;1439901-97-9
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| PubChem CID |
89455219
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
714.0±70.0 °C at 760 mmHg
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| Flash Point |
385.6±35.7 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.677
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| LogP |
1.82
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
34
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| Complexity |
751
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C=CC(=O)N1CCC[C@@H](C1)N2C3=NC=NC(=C3N(C2=O)C4=CC=C(C=C4)OC5=CC=CC=C5)N
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| InChi Key |
KSUDUUBCXJUFRL-SFHVURJKSA-N
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| InChi Code |
InChI=1S/C25H24N6O3/c1-2-21(32)29-14-6-7-18(15-29)31-24-22(23(26)27-16-28-24)30(25(31)33)17-10-12-20(13-11-17)34-19-8-4-3-5-9-19/h2-5,8-13,16,18H,1,6-7,14-15H2,(H2,26,27,28)/t18-/m0/s1
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| Chemical Name |
(S)-9-(1-acryloylpiperidin-3-yl)-6-amino-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.48 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear 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 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: 2.5 mg/mL (5.48 mM) 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; with ultrasonication. 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. View More
Solubility in Formulation 3: 2.5 mg/mL (5.48 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1906 mL | 10.9529 mL | 21.9058 mL | |
| 5 mM | 0.4381 mL | 2.1906 mL | 4.3812 mL | |
| 10 mM | 0.2191 mL | 1.0953 mL | 2.1906 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 |
| NCT03100942 | Completed | Drug: Lanraplenib Drug: Filgotinib |
Sjogren's Syndrome | Gilead Sciences | May 1, 2017 | Phase 2 |
| NCT02626026 | Completed | Drug: Tirabrutinib Drug: Placebo |
Rheumatoid Arthritis | Gilead Sciences | January 26, 2016 | Phase 1 |
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