ONO-4059 - CAS 1351636-18-4
Catalog number: 1351636-18-4
Category: Inhibitor
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Molecular Formula:
Molecular Weight:
ONO-4059, a BTK inhibitor, has been found to have potential effect against sorts of malignancies by influencing the B-cell development. It is currently under Phase II trail to study its effect against Chronic lymphocytic leukaemia. IC50: 2.2 nM.
Related CAS:
1439901-97-9 (HCl); 1351635-67-0 (ONO-4059-analog)
White to off white powder
(R)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7,9-dihydro-8H-purin-8-one; ONO-4059; ONO4059; ONO 4059; ONO-4059; GS 4059; GS-4059; GS4059; ONO-WG-307; Tirabrutinib
Soluble in DMSO, not in water
-20ºC Freeze
ONO-4059 is a BTK inhibitor that has been found to have potential effect against sorts of malignancies by influencing the B-cell development.
Shelf Life:
As supplied, 2 years from the QC date provided on the Certificate of Analysis, when stored properly
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Current Developer:
Gilead Sciences; Ono Pharmaceutical
1.Sensitive Detection of the Natural Killer Cell-Mediated Cytotoxicity of Anti-CD20 Antibodies and Its Impairment by B-Cell Receptor Pathway Inhibitors.
Hassenrück F;Knödgen E;Göckeritz E;Midda SH;Vondey V;Neumann L;Herter S;Klein C;Hallek M;Krause G Biomed Res Int. 2018 Mar 19;2018:1023490. doi: 10.1155/2018/1023490. eCollection 2018.
The antibody-dependent cell-mediated cytotoxicity (ADCC) of the anti-CD20 monoclonal antibodies (mAbs) rituximab and obinutuzumab against the cell line Raji and isolated CLL cells and its potential impairment by kinase inhibitors (KI) was determined via lactate dehydrogenase release or calcein retention, respectively, using genetically modified NK92 cells expressing CD16-176V as effector cells. Compared to peripheral blood mononuclear cells, recombinant effector cell lines showed substantial alloreactivity-related cytotoxicity without addition of mAbs but afforded determination of ADCC with reduced interassay variability. The cytotoxicity owing to alloreactivity was less susceptible to interference by KI than the ADCC of anti-CD20 mAbs, which was markedly diminished by ibrutinib, but not by idelalisib. Compared to rituximab, the ADCC of obinutuzumab against primary CLL cells showed approximately 30% higher efficacy and less interference with KI. Irreversible BTK inhibitors at a clinically relevant concentration of 1 ;μ;M only weakly impaired the ADCC of anti-CD20 mAbs, with less influence in combinations with obinutuzumab than with rituximab and by acalabrutinib than by ibrutinib or tirabrutinib.
2.Responses to the Selective Bruton's Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines.
Kozaki R;Vogler M;Walter HS;Jayne S;Dinsdale D;Siebert R;Dyer MJS;Yoshizawa T Cancers (Basel). 2018 Apr 23;10(4). pii: E127. doi: 10.3390/cancers10040127.
Bruton's tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi) are infrequent, highlighting the need to identify mechanisms of resistance to BTKi as well as predictive biomarkers. We investigated the response to the selective BTKi, tirabrutinib, in a panel of 64 hematopoietic cell lines. Notably, only six cell lines were found to be sensitive. Although activated B-cell type DLBCL cells were most sensitive amongst all cell types studied, sensitivity to BTKi did not correlate with the presence of activating mutations in the BCR pathway. To improve efficacy of tirabrutinib, we investigated combination strategies with 43 drugs inhibiting 34 targets in six DLBCL cell lines. Based on the results, an activated B-cell-like (ABC)-DLBCL cell line, TMD8, was the most sensitive cell line to those combinations, as well as tirabrutinib monotherapy. Furthermore, tirabrutinib in combination with idelalisib, palbociclib, or trametinib was more effective in TMD8 with acquired resistance to tirabrutinib than in the parental cells.
3.Homogeneous BTK Occupancy Assay for Pharmacodynamic Assessment of Tirabrutinib (GS-4059/ONO-4059) Target Engagement.
Yu H;Truong H;Mitchell SA;Liclican A;Gosink JJ;Li W;Lin J;Feng JY;Jürgensmeier JM;Billin A;Xu R;Patterson S;Pagratis N SLAS Discov. 2018 Jul 1:2472555218786165. doi: 10.1177/2472555218786165. [Epub ahead of print]
Bruton's tyrosine kinase (BTK) is a clinically validated target for B-cell leukemias and lymphomas with FDA-approved small-molecule inhibitors ibrutinib and acalabrutinib. Tirabrutinib (GS-4059/ONO-4059, Gilead Sciences, Inc., Foster City, CA) is a second-generation, potent, selective, irreversible BTK inhibitor in clinical development for lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). An accurate pharmacodynamic assay to assess tirabrutinib target coverage in phase 1/2 clinical studies will inform dose and schedule selection for advanced clinical evaluation. We developed a novel duplex homogeneous BTK occupancy assay based on time-resolved fluorescence resonance energy transfer (TR-FRET) to measure free and total BTK levels in a multiplexed format. The dual-wavelength emission property of terbium-conjugated anti-BTK antibody served as the energy donor for two fluorescent energy acceptors with distinct excitation and emission spectra. The assay was characterized and qualified using full-length purified recombinant human BTK protein and peripheral blood mononuclear cells derived from healthy volunteers and patients with CLL.
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