生物活性

• 靶点	BTK IC50:2.2nM

• 描述BTK (Bruton Tyrosine Kinase) is a cytoplasmic, non-receptor tyrosine kinase that transmits signals from a variety of cell-surface molecules, including the B-cell receptor (BCR) and tissue homing receptors. BTK is indispensable for B lymphocyte development, differentiation and signaling, and plays a crucial role in B-cell development^[3]. ONO-4059 is a BTK inhibitor. The IC50 of ONO-4059 against BTK kinase was 2.2 nM^[3]. ONO-4059 inhibited the TMD-8 cell growth with the IC50 of 3.59 nM for 72h as determined by a cell viability assay. ONO-4059 also concentration-dependently inhibited BTK phosphorylation with the IC50 of 23.9 nM for 4h^[4]. In a TMD-8 xenograft model established in SCID mice, ONO-4059 was administered orally or mixed in food at doses up to 20 mg/kg/day and animals were dosed QD or BD. For the groups that treatment started when tumor volume was 100 - 200mm³, tumor growth inhibition of ONO-4059 treated groups was 23% in QD, 72.9% in BD and 100% in dose mixed in food, respectively. For the groups that treatment started when tumor volume was 400 - 450mm³, no growth inhibition was observed in the QD group and growth inhibitions of 27.5% in BD and 100% in dose mixed in food were observed^[5]. In another study of TMD-8 xenograft model, ONO-4059 was administered via mixed diet at an indicated relative content of 0.0037%. This dose resulted in tumor growth inhibition of 56.1% as a single agent and significantly enhanced the anti-tumor activity of Rituximab^[6].

• 动物研究
  剂量	Mice: 3 mg/kg - 30 mg/kg[3] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03740529	Chronic Lymphocytic Leukemia ... more >> Waldenstrom's Macroglobulinemia Mantle Cell Lymphoma Marginal Zone Lymphoma B-cell Lymphoma Small Lymphocytic Lymphoma Collapse <<	Phase 1 Phase 2	Recruiting	April 2021	United States, Tennessee ... more >> Sarah Cannon Research Institute at Tennessee Oncology Recruiting Nashville, Tennessee, United States, 37203 Contact: Ian W Flinn, MD, PhD Collapse <<
  NCT02968563	Chronic Lymphocytic Leukemia	Phase 2	Recruiting	February 2024	Germany ... more >> Recruiting Mutlangen, Baden-Wuerttemberg, Germany Recruiting Ravensburg, Baden-Wuerttemberg, Germany Recruiting Tübingen, Baden-Württemberg, Germany Recruiting Ulm, Baden-Württemberg, Germany Recruiting Augsburg, Bavaria, Germany Recruiting München, Bavaria, Germany Recruiting Erlangen, Bayern, Germany Recruiting München, Bayern, Germany Recruiting Regensburg, Bayern, Germany Withdrawn Wurzburg, Bayern, Germany Recruiting Frankfurt, Brandenburg, Germany Recruiting Gießen, Hessen, Germany Recruiting Koln, Nordrhein-Westfalen, Germany Recruiting Mönchengladbach, Nordrhein-Westfalen, Germany Recruiting Paderborn, Nordrhein-Westfalen, Germany Recruiting Neunkirchen, Saarland, Germany Recruiting Leipzig, Sachsen, Germany Recruiting Kiel, Schleswig-Holstein, Germany Recruiting Luebeck, Germany Recruiting Mannheim, Germany Withdrawn Muenchen, Germany Collapse <<
  NCT02457559	Relapsed/Refractory B-cell Mal... more >>ignancies Collapse <<	Phase 1	Active, not recruiting	October 2019	France ... more >> CHRU de Lille Lille, France, 59037 Hopital Saint Eloi Montpellier, France, 34295 Centre Hospitalier Lyon Sud Pierre Benite, France, 69310 United Kingdom University Hospital of Wales Cardiff, United Kingdom, CF14 4XW Leicester Royal Infirmary Leicester, United Kingdom, LE1 5WW Derriford Hospital Plymouth, United Kingdom, PL6 8BG Collapse <<

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• 参考文献

• [1] Walter HS, Rule SA, et al. 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.

  [2] Burger JA. Bruton's tyrosine kinase (BTK) inhibitors in clinical trials. Curr Hematol Malig Rep. 2014 Mar;9(1):44-9.

  [3] Burger JA. Bruton's tyrosine kinase (BTK) inhibitors in clinical trials. Curr Hematol Malig Rep. 2014 Mar;9(1):44-9.

  [4] ONO-4059, A Novel Bruton’s Tyrosine Kinase (Btk) Inhibitor: Synergistic Activity In Combination With Chemotherapy In a ABC-DLBCL Cell Line

  [5] ONO-4059—a Potent and Selective Reversible Bruton’s Tyrosine Kinase (Btk) Inhibitor: Single Agent, Twice Daily (BD) Dosing and Dosing with Food Results in Sustained, High Trough Levels of ONO-4059, Translating into 100% Tumour Remission in a TMD-8 Xenograft Model

  [6] Yasuhiro T, Sawada W, Klein C, Kozaki R, Hotta S, Yoshizawa T. 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. Leuk Lymphoma. 2017 Mar;58(3):699-707.

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