生物活性

• 靶点	Aurora Kinase B IC50:0.37nM

• 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. AZD1152-HQPA, the active drug form converted from AZD1152 (Barasertib) in human plasma, is a specific Aurora B inhibitor with Ki value of 0.36nM versus 1369nM for A kinase. Consistent with Aurora B kinase inhibition, treatment with AZD1152-HQPA caused a dose-dependent inhibition of histone H3 phosphorylation on Ser10 site, with IC50 of 10.27nM, in SW620 colorectal tumor cells and led to increased polyploidy following a 48-h exposure. This activity of AZD1152-HQPA can also observed in an in vivo study. Administration of AZD1152 at dose ranging in 10-150mg/kg/d via an osmotic mini-pump for 48h inhibited growth in a panel of human tumor xenografts, including SW620, Colo205, A549 and HL-6, suggesting that AZD1152 was active against a variety of solid tumors including colon, breast and lung cancers^[1]. AZD1152 also had effect in hematologic malignancies. In the presence of AZD1152-HQPA, the clonogenic growth of freshly isolated leukemia cells tested was effectively inhibited with IC50 values ranging in 1-3nM. Exposure of MOLM13 cells to AZD1152-HQPA (1-10nM) for 24 or 48 hours induced apoptosis in a dose-dependent manner. AZD1152-HQPA alone or combined with vincristine or daunorubicin significantly inhibited the proliferation of MOLM13 cells in murine xenograft model^[2].
• 作用机制AZD1152-HQPA can bind to the ATP-binding pocket of Aurora B.^[2]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  BALM-14	12.5/25/50 nM	Apoptosis Assay	48 h	increases the levels of the cleaved forms of PARP and caspase 3	19823168
  BALM-27	12.5/25/50 nM	Apoptosis Assay	48 h	increases the levels of the cleaved forms of PARP and caspase 3	19823168
  BJAJ	500 nM	Growth Inhibition Assay	0-72 h	inhibits cell growth significantly	21371446

• 更多

• 动物研究
  剂量	Mice: min = 5 mg/kg[2], max = 100 mg/kg[4]
  给药途径	i.p.

• 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
  NCT03217838	Acute Myeloid Leukaemia ... more >> High-Risk Myelodysplastic Syndrome Collapse <<	Phase 1 Phase 2	Recruiting	August 13, 2021	United States, Colorado ... more >> Research Site Recruiting Denver, Colorado, United States, 80218 United States, Florida Research Site Recruiting Sarasota, Florida, United States, 34232 United States, Michigan Research Site Recruiting Detroit, Michigan, United States, 48201 United States, Oklahoma Research Site Recruiting Oklahoma City, Oklahoma, United States, 73104 United States, Tennessee Research Site Recruiting Nashville, Tennessee, United States, 37203 United States, Wisconsin Research Site Recruiting Milwaukee, Wisconsin, United States, 53051 Collapse <<
  NCT00926731	Acute Myeloid Leukemia	Phase 1	Completed	-	United States, Ohio ... more >> Research Site Cleveland, Ohio, United States United States, Texas Research Site Houston, Texas, United States France Research Site Le Chesnay Cedex, France Research Site Villejuif Cedex, France Collapse <<
  NCT01019161	Acute Myeloid Leukaemia	Phase 1	Completed	-	United Kingdom ... more >> Research Site Manchester, United Kingdom Collapse <<

• 参考文献

• [1] Wilkinson RW, Odedra R, et al. AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res. 2007 Jun 15;13(12):3682-8.

  [2] Yang J, Ikezoe T, et al. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood. 2007 Sep 15;110(6):2034-40. Epub 2007 May 10.

  [3] Sessa F, Villa F, et al. Structure of Aurora B-INCENP in complex with barasertib reveals a potential transinhibitory mechanism. Acta Crystallogr F Struct Biol Commun. 2014 Mar;70(Pt 3):294-8.

  [4] Helfrich BA, Kim J, et al. Barasertib (AZD1152), a Small Molecule Aurora B Inhibitor, Inhibits the Growth of SCLC Cell Lines In Vitro and In Vivo. Mol Cancer Ther. 2016;15(10):2314-2322.