Tirabrutinib free base
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MedKoo CAT#: 206611

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.


Chemical Structure

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Tirabrutinib free base
CAS# 1351636-18-4 (free base)

Theoretical Analysis

MedKoo Cat#: 206611
Name: Tirabrutinib free base
CAS#: 1351636-18-4 (free base)
Chemical Formula: C25H22N6O3
Exact Mass: 454.1753
Molecular Weight: 454.49
Elemental Analysis: C, 66.07; H, 4.88; N, 18.49; O, 10.56

Price and Availability

Size Price Availability Quantity
10.0mg USD 90.0 Ready to ship
25.0mg USD 150.0 Ready to ship
50.0mg USD 250.0 Ready to ship
100.0mg USD 450.0 Ready to ship
200.0mg USD 850.0 Ready to ship
500.0mg USD 1650.0 Ready to ship
1.0g USD 2850.0 2 Weeks
2.0g USD 4650.0 2 Weeks
5.0g USD 7450.0 2 Weeks
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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

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/

Solubility Data

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 2.2

Preparing Stock Solutions

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.

Recalculate based on batch purity %
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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1: Barrientos JC. Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential. Onco Targets Ther. 2016 May 18;9:2945-53. doi: 10.2147/OTT.S102573. eCollection 2016. Review. PubMed PMID: 27274288; PubMed Central PMCID: PMC4876096.

2: 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.

3: 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.

4: 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.

5: 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.

6: 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.



Additional Information

Related CAS#
1439901-97-9 (ONO-4059 HCl);
1351636-18-4 (ONO-4059 free base).
1351635-67-0 (ONO-4059 analog)