Synonym
ONO4059-Analog; ONO 4059-Analog; ONO-4059-Analog; GS 4059-Analog; GS-4059-Analog; GS4059-Analog.
IUPAC/Chemical Name
(S)-9-(1-acryloylpiperidin-3-yl)-6-amino-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one
InChi Key
KSUDUUBCXJUFRL-SFHVURJKSA-N
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
SMILES Code
O=C1N(C2=CC=C(C=C2)OC3=CC=CC=C3)C4=C(N)N=CN=C4N1[C@@H]5CN(C(C=C)=O)CCC5
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Note: As of 5/19/2016, Sci-Finder listed ONO4059 has CAS#1351635-67-0.
In a recent paper ( Blood. 2016 Jan 28;127(4):411-9.), ONO-4059 has 1351636-18-4
We consider the structure in paper (( Blood. 2016 Jan 28;127(4):411-9.) is more reliable. Thus we rename CAS#1351635-67-0 as ONO4059-analog
Biological target:
ONO-4059 analog is the analog of ONO-4059, ONO-4059 is a highly potent and selective Btk inhibitor.
In vitro activity:
In vitro kinase assays showed that, compared with ibrutinib, tirabrutinib and other second-generation BTK inhibitors demonstrated a highly selective kinase profile. Data from in vitro cellular systems showed that tirabrutinib selectively affected B-cells. Tirabrutinib inhibited the cell growth of both TMD8 and U-2932 cells in correlation with the inhibition of BTK autophosphorylation.
Reference: PLoS One. 2023 Mar 10;18(3):e0282166. https://pubmed.ncbi.nlm.nih.gov/36897912/
In vivo activity:
The RANKL model studies show that tirabrutinib significantly suppressed bone loss with the inhibition of serum TRAPCP5b and urinary CTX-1. Bone Mineral Density (BMD) loss in tirabrutinib-treated mice was 55% (P < .05), 87% (P < .001) and 88% (P < .001) for the 3, 10 and 30 mg/kg dose groups respectively. Btk and Tec are required for osteoclast differentiation and activation based on the genetic evidence obtained from Btk and Tec double deficient mice. Tirabrutinib may be a novel therapeutic target for bone diseases, such as osteoporosis and RA.
Reference: Bone Rep. 2019 Mar 15;10:100201. https://pubmed.ncbi.nlm.nih.gov/30956999/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMF |
25.0 |
54.76 |
| DMF:PBS (pH 7.2) (1:1) |
0.5 |
1.10 |
| DMSO |
35.0 |
76.67 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
456.51
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Kozaki R, Yasuhiro T, Kato H, Murai J, Hotta S, Ariza Y, Sakai S, Fujikawa R, Yoshida T. Investigation of the anti-tumor mechanism of tirabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, by phosphoproteomics and transcriptomics. PLoS One. 2023 Mar 10;18(3):e0282166. doi: 10.1371/journal.pone.0282166. PMID: 36897912; PMCID: PMC10004634.
2. Das S, Bar-Sagi D. BTK signaling drives CD1dhiCD5+ regulatory B-cell differentiation to promote pancreatic carcinogenesis. Oncogene. 2019 Apr;38(17):3316-3324. doi: 10.1038/s41388-018-0668-3. Epub 2019 Jan 11. PMID: 30635655; PMCID: PMC6486434.
3. Ariza Y, Murata M, Ueda Y, Yoshizawa T. Bruton's tyrosine kinase (Btk) inhibitor tirabrutinib suppresses osteoclastic bone resorption. Bone Rep. 2019 Mar 15;10:100201. doi: 10.1016/j.bonr.2019.100201. PMID: 30956999; PMCID: PMC6431727.
In vitro protocol:
1. Kozaki R, Yasuhiro T, Kato H, Murai J, Hotta S, Ariza Y, Sakai S, Fujikawa R, Yoshida T. Investigation of the anti-tumor mechanism of tirabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, by phosphoproteomics and transcriptomics. PLoS One. 2023 Mar 10;18(3):e0282166. doi: 10.1371/journal.pone.0282166. PMID: 36897912; PMCID: PMC10004634.
2. Das S, Bar-Sagi D. BTK signaling drives CD1dhiCD5+ regulatory B-cell differentiation to promote pancreatic carcinogenesis. Oncogene. 2019 Apr;38(17):3316-3324. doi: 10.1038/s41388-018-0668-3. Epub 2019 Jan 11. PMID: 30635655; PMCID: PMC6486434.
In vivo protocol:
1. Kozaki R, Yasuhiro T, Kato H, Murai J, Hotta S, Ariza Y, Sakai S, Fujikawa R, Yoshida T. Investigation of the anti-tumor mechanism of tirabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, by phosphoproteomics and transcriptomics. PLoS One. 2023 Mar 10;18(3):e0282166. doi: 10.1371/journal.pone.0282166. PMID: 36897912; PMCID: PMC10004634.
2. Ariza Y, Murata M, Ueda Y, Yoshizawa T. Bruton's tyrosine kinase (Btk) inhibitor tirabrutinib suppresses osteoclastic bone resorption. Bone Rep. 2019 Mar 15;10:100201. doi: 10.1016/j.bonr.2019.100201. PMID: 30956999; PMCID: PMC6431727.
1: Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016 Mar 9;9:21. doi: 10.1186/s13045-016-0250-9. PubMed PMID: 26957112; PubMed Central PMCID: PMC4784459.
2: Walter HS, Rule SA, Dyer MJ, Karlin L, Jones C, Cazin B, Quittet P, Shah N, Hutchinson CV, Honda H, Duffy K, Birkett J, Jamieson V, Courtenay-Luck N, Yoshizawa T, Sharpe J, Ohno T, Abe S, Nishimura A, Cartron G, Morschhauser F, Fegan C, Salles G. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016 Jan 28;127(4):411-9. doi: 10.1182/blood-2015-08-664086. Epub 2015 Nov 5. PubMed PMID: 26542378; PubMed Central PMCID: PMC4731845.
3: Robak P, Smolewski P, Robak T. Emerging immunological drugs for chronic lymphocytic leukemia. Expert Opin Emerg Drugs. 2015 Sep;20(3):423-47. doi: 10.1517/14728214.2015.1046432. Epub 2015 Jul 11. Review. PubMed PMID: 26153226.
4: Burger JA. Bruton's tyrosine kinase (BTK) inhibitors in clinical trials. Curr Hematol Malig Rep. 2014 Mar;9(1):44-9. doi: 10.1007/s11899-013-0188-8. Review. PubMed PMID: 24357428.
4: Akinleye A, Chen Y, Mukhi N, Song Y, Liu D. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol. 2013 Aug 19;6:59. doi: 10.1186/1756-8722-6-59. Review. PubMed PMID: 23958373; PubMed Central PMCID: PMC3751776.
