生物活性

• 靶点

  Aurora Kinase A IC50:13nM

  Aurora Kinase B IC50:79nM

  Aurora Kinase C IC50:61nM

• 描述The Aurora family of serine/threonine kinases, which consists of Aurora A, B and C, plays an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Danusertib is pan-Aurora inhibitor with IC50 values of 13, 79, and 61 nM for Aurora A, B, and C (measured by in vitro kinase assays), respectively, also shows inhibitory effect on Abl, TrkA, c-RET and FGFR1 with IC50 values of 25nM, 31nM, 31nM and 47nM, respectively. Treatment with Danusertib below 10μM inhibited autophosphorylation in position Thr288 of Aurora A and histone H3 in position Ser10, the substrate of Aurora B, suggesting the cellular inhibition on Aurora A and Aurora B kinase activity by Danusertib in HeLa cells. Consistent with the in vitro kinase assays, the inhibition on c-RET, TrkA and FGFR1 by Danusertib can be observed, performing by the decreased pRet-Y905 in TT cells, decreased pTrkA-Y490 induced by NGF in PC-12 cells and decreased pERK1/2 of FGFR1 downstream induced by FGF not EGF in NIH-3T3 cells. Danusertib showed widely antiproliferative effect with IC50 values ranging in 28-300nM in several tumor cell lines covering different histotypes, including colon, breast, prostate, lung, and ovary. This anti-proliferation by Danusertib may due to both inhibition of Aurora B and defects of the p53-p21–dependent postmitotic checkpoint, and these markers can also be observed in in vivo study. Administration of Danusertib at dose of 25-30 mg/kg, i.v., bd, showed antitumor activity in several human tumor xenograft models, including HL-60, A2780, HCT-116, DMBA-induced mammary carcinoma, MMTV-RAS transgenic mammary carcinoma and TRAMP transgenic prostate carcinoma^[1].
• 作用机制Danusertib is a small molecule ATP competitive pan-aurora kinase inhibitor.^[2]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A2780 cells	-	Proliferation assay	-	Antiproliferative activity against A2780 cells, IC50=28 nM	17125279
  HCT116 cells	-	Proliferation assay	-	Antiproliferative activity against HCT116 cells, IC50=31 nM	17125279
  HCT116 cells	-	Function assay	-	Cell cycle arrest in HCT116 cells by accumulation at G2/M phase, EC50=80 nM	17125279

• 更多

• 动物研究
  剂量	Mice: 15 mg/kg[3] (i.p.), 100 mg/kg[3] (p.o.)
  给药途径	i.p., 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
  NCT00335868	Leukemia	Phase 2	Unknown	-	United States, California ... more >> Jonsson Comprehensive Cancer Center at UCLA Los Angeles, California, United States, 90095-1781 Collapse <<
  NCT00766324	Metastatic Hormone Refractory ... more >>Prostate Cancer Collapse <<	Phase 2	Completed	-	Italy ... more >> Nerviano Medical Sciences. Clinical Research Dept. Nerviano, Milano, Italy, 20014 Collapse <<
  NCT00872300	Multiple Myeloma	Phase 2	Terminated(Low recruitment rat... more >>e) Collapse <<	-	United States, Arizona ... more >> MAYO Clinic Scottsdale, Arizona, United States, 85259 United States, Illinois The Robert H Lurie Comprehensive Cancer Center, Northwestern University Chicago, Illinois, United States, 60611 France Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille Lille, France, 59037 University Hospital Hôtel-Dieu Nantes, France, 44093 Collapse <<

• 参考文献

• [1] Carpinelli P, Ceruti R, et al. PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3158-68.

  [2] Borthakur G, Dombret H, et al. A phase I study of danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy. Haematologica. 2015 Jul;100(7):898-904.