In vitro: ONO-4059 covalently binds to BTK, and reversibly blocks BCR signaling and B-cell proliferation and activation. It has greater selectivity for BTK than Lck, Fyn, LynA and ONO/GS-4059 only inhibits anti-IgM-induced B-cell activation in a concentration-dependent manner but not inhibit anti-CD3/CD28-induced activation of T-lymphocytes from human PBMCs. ONO/GS-4059 inhibits cell proliferation in some malignant B-cell lines but also induces classical apoptosis at nanomolar concentration in the activated-B cell (ABC) DLBCL cell line, TMD8.
In vivo: ONO-4059 demonstrates therapeutic efficacy in a mouse CIA model by suppressing generation of inflammatory chemokines and cytokines including IL-6, IL-8, and TNFα by monocytes, and accompanied by regression of cartilage erosion, bone damage, and pannus formation. In pre-clinical models, and in the clinic in both CLL and NHL patients, It exerts its anti-tumour activity, with a favourable safety profile along with promising efficacy over a long duration.
|Cell lines||DLBCL cell lines TMD8 cells|
|Preparation method||Cells are treated with idelalisib (420 nM), ONO/GS-4059 (320 nM) or in combination for 48 hours and apoptosis is assessed by FITC Annexin V staining, and measured by flow cytometry.|
|Incubation time||48 h|
|Animal models||Male CB17-SCID mice|
|Formulation||5% (v/v) N-Methyl-2-pyrrolidone (NMP) / 55% (v/v) Polyethylene Glycol 300 (PEG) 300 / 40% (v/v) Water / 1% (w/v) Vitamin E D-α-Tocopherol Polyethylene Glycol 1000 Succinate (TPGS)|
|Dosages||5 and 10 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||98 mg/mL in DMSO|
PI3Kδ inhibitor idelalisib in combination with BTK inhibitor ONO/GS-4059 in diffuse large B cell lymphoma with acquired resistance to PI3Kδ and BTK inhibitors.
Yahiaoui A, et al. PLoS One. 2017 Feb 8;12(2):e0171221. PMID: 28178345.
Bruton tyrosine kinase inhibitor ONO/GS-4059: from bench to bedside.
Wu J, et al. Oncotarget. 2017 Jan 24;8(4):7201-7207. PMID: 27776353.
Anti-tumor efficacy study of the Bruton's tyrosine kinase (BTK) inhibitor, ONO/GS-4059, in combination with the glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab (GA101) demonstrates superior in vivo efficacy compared to ONO/GS-4059 in combination with rituximab.
Yasuhiro T, et al. Leuk Lymphoma. 2017 Mar;58(3):699-707. PMID: 27684575.
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Orelabrutinib is an orally active and irreversible inhibitor of Bruton's tyrosine kinase (BTK).
Zanubrutinib (BGB-3111) is a potent and highly selective small molecule inhibitor of Bruton's tyrosine kinase (BTK).
ARQ 531 is a potent reversible inhibitor of BTK (IC50 = 0.85 nM), exhibits potent antitumor activity in ibrutinib-resistant diffuse large B-cell lymphoma.
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