WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H206611
CAS#: 1351636-18-4 (free base)
Description: Tirabrutinib, also known as ONO-4059 and GS-4059, is a potent and orally active Bruton agammaglobulinemia tyrosine kinase (BTK) in hibitor. Upon administration, ONO-4059 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.
Hodoodo Cat#: H206611
Name: Tirabrutinib free base
CAS#: 1351636-18-4 (free base)
Chemical Formula: C25H22N6O3
Exact Mass: 454.18
Molecular Weight: 454.490
Elemental Analysis: C, 66.07; H, 4.88; N, 18.49; O, 10.56
Related CAS #: 1439901-97-9 (HCl) 1351636-18-4 (free base) 1351635-67-0 (ONO-4059-analog)
Synonym: ONO-4059; ONO4059; ONO 4059; ONO-4059; GS 4059; GS-4059; GS4059; ONO-WG-307; Tirabrutinib
IUPAC/Chemical Name: (R)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one
InChi Key: SEJLPXCPMNSRAM-GOSISDBHSA-N
InChi Code: InChI=1S/C25H22N6O3/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)/t18-/m1/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#CC)=O)CC5
Appearance: White to off white powder
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
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: Related CAS# 1439901-97-9 (ONO-4059 HCl); 1351636-18-4 (ONO-4059 free base). 1351635-67-0 (ONO-4059 analog)
Biological target: | Tirabrutinib (ONO-4059) is a BTK inhibitor with an IC50 of 2.2 nM. |
In vitro activity: | To assess the susceptibility of B-cell malignancies to tirabrutinib, a panel of 64 hematopoietic cell lines, including 10 GCB-DLBCL and 11 ABC-DLBCL lines, was screened (Table 1). Six showed a response to tirabrutinib when concentrations up to 10,000 nM were used; four of these were derived from ABC-type DLBCL (TMD8 with EC50 of 4.5 nM; OCI-LY10, U2932, and HBL1 each with an EC50 of approximately 3000 nM). The other responding cell lines were Pfeiffer, a GCB-DLBCL with an EC50 of around 3000 nM, and REC1, an MCL line with an EC50 of 33 nM. The cell line most sensitive to tirabrutinib was the CD79B mutant cell line TMD8. Reference: Cancers (Basel). 2018 Apr; 10(4): 127. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923382/ |
In vivo activity: | As illustrated in Fig 1a, b and Supplementary Figure S1a, inflammatory stimulation of splenic B cells from naïve mice upregulated BTK activation as measured by pBTK (Y223) expression. Cytokine treatment of B cells did not alter total BTK protein levels (Supplementary Fig. S1a). This increase was accompanied by an expansion of the CD1dhiCD5+ Breg population (Fig. 1c, 1d). Significantly, inhibition of BTK activation by tirabrutinib (Fig. 1a, 1b, Supplementary Fig. S1a) attenuated cytokine-induced CD1dhiCD5+ Breg differentiation (Fig. 1c, 1d). Furthermore, tirabrutinib markedly downregulated expression of both CD1dhiCD5+ Breg functional markers, IL-10 (Fig. 1e, Supplementary Fig. S1b) and IL-35 (heterodimer of Ebi3 and p35, encoded by the Ebi3 and IL12A genes, respectively) (Fig. 1f, 1g), which are critical mediators of CD1dhiCD5+ Breg immunosuppressive function. Collectively, these results directly implicate the BTK signaling pathway in promoting CD1dhiCD5+ Breg differentiation and production of the immunomodulatory cytokines IL-10 and IL-35. Reference: Oncogene. 2019 Apr;38(17):3316-3324. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486434/ |
Solvent | Max Conc. mg/mL | Max Conc. mM | |
---|---|---|---|
Solubility | |||
DMSO | 65.0 | 143.02 | |
DMSO:PBS (pH 7.2) (1:2) | 0.3 | 0.66 | |
DMF | 30.0 | 66.01 | |
Ethanol | 1.0 | 2.20 |
The following data is based on the product molecular weight 454.49 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, Vogler M, Walter HS, Jayne S, Dinsdale D, Siebert R, Dyer MJS, Yoshizawa T. 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. doi: 10.3390/cancers10040127. PMID: 29690649; PMCID: PMC5923382. 2. Hofland T, de Weerdt I, Ter Burg H, de Boer R, Tannheimer S, Tonino SH, Kater AP, Eldering E. Dissection of the Effects of JAK and BTK Inhibitors on the Functionality of Healthy and Malignant Lymphocytes. J Immunol. 2019 Oct 15;203(8):2100-2109. doi: 10.4049/jimmunol.1900321. Epub 2019 Sep 11. PMID: 31511358. 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. 4. 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 vitro protocol: | 1. Kozaki R, Vogler M, Walter HS, Jayne S, Dinsdale D, Siebert R, Dyer MJS, Yoshizawa T. 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. doi: 10.3390/cancers10040127. PMID: 29690649; PMCID: PMC5923382. 2. Hofland T, de Weerdt I, Ter Burg H, de Boer R, Tannheimer S, Tonino SH, Kater AP, Eldering E. Dissection of the Effects of JAK and BTK Inhibitors on the Functionality of Healthy and Malignant Lymphocytes. J Immunol. 2019 Oct 15;203(8):2100-2109. doi: 10.4049/jimmunol.1900321. Epub 2019 Sep 11. PMID: 31511358. |
In vivo protocol: | 1. 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. 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. |
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