生物活性

• 靶点	Aurora Kinase A IC50:1.2nM

• 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. Alisertib is a selective Aurora A kinase inhibitor with IC50 value of 1.2nM versus 396.5nM for Aurora B (measured by enzymatic assay). Consistent with inhibition by Aurora A on cell phenotype, treatment with 50nM Alisertib casued an increase in cells in the G2/M phase at 24 and 48 hours in HCT-116 cells, as well as caused mitotic spindle abnormalities and chromosome misalignment in cells. However, at a higher concentration of 0.25 or 1μM, Alisertib caused an increase in the number of cells with 8N DNA content and multinuclear in cells, as phenotypes consistent with Aurora B inhibition. Alisertib can inhibit cell proliferation, including HCT-116, SW480, DLD-1, H460, MDA-MB-231, PC3, SKOV3, HPAC, OCI-LY-3, OCI-LY-7, OCI-LY-10, OCI-LY-19 and WSU cell lines, with IC50 values ranging in 15-469nM, suggesting its widely anti-proliferative effect on colon, lung, breast, prostate, ovarian, pancreatic and lymphoma tumor. Alisertib possessed good pharmacodynamics as orally dosed at 3, 10, and 30mg/kg with Alisertib resulted in a time- and dose-dependent increase in the mitotic marker p-HisH3, suggesting Aurora A inhibition, in tumor tissue from HCT-116 xenografts. Misaligned chromosomes and reduced bipolar mitotic spindles can also be observed. Oral administration of Alisertib at 3, 10, and 30 mg/kg once daily for 21 consecutive days dose-dependently inhibit tumor growth in nude mice bearing subcutaneous HCT-116 tumors. The broad antitumor activity of Alisertib can also be observed in a diverse set of solid tumor xenograft models as well as regressions in in vivo models of lymphoma, including the cell lines mentioned above^[1].
• 作用机制Alisertib binds Aurora-A at the ATP-binding pocket.^[2]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  2884	100 μM	Growth Inhibition Assay	72 h	Attenuates cell growth	23328114
  2885	100 μM	Growth Inhibition Assay	72 h	Attenuates cell growth	23328114
  A172	100 μM	Cytotoxic Assay	24 h	IC50=0.120 μM	22274399

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• 动物研究
  剂量	Mice: min = 3mg/kg, max =30 mg/kg[1]
  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
  NCT02551055	Neoplasms, Advanced or Metasta... more >>tic Collapse <<	Phase 1	Terminated(Business Decision; ... more >>No Safety Or Efficacy Concerns.) Collapse <<	-	United States, New York ... more >> Lake Success, New York, United States New York, New York, United States United States, Pennsylvania Philadelphia, Pennsylvania, United States United States, Texas Dallas, Texas, United States Houston, Texas, United States Spain Barcelona, Spain Collapse <<
  NCT01540682	Head and Neck Cancer	Phase 1	Completed	-	United States, Pennsylvania ... more >> Abramson Cancer Center of the University of Pennsylvania Philadelphia, Pennsylvania, United States, 19104 Collapse <<
  NCT01316692	Recurrent Melanoma ... more >> Stage IIIc Melanoma Stage IV Melanoma Collapse <<	Phase 2	Terminated(low accrual)	-	United States, Tennessee ... more >> Vanderbilt-Ingram Cancer Center Nashville, Tennessee, United States, 37232-6838 Collapse <<

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• 参考文献

• [1] Manfredi MG, Ecsedy JA, et al. Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res. 2011;17(24):7614-24.

  [2] Asteriti IA, Daidone F, et al. Identification of small molecule inhibitors of the Aurora-A/TPX2 complex. Oncotarget. 2017;8(19):32117-32133.