生物活性

• 靶点	KSP Ki:1.7nM

• 描述Kinesins are motor proteins that have various of cellular physiologies, including mitosis, meiosis and cellular cargo transportation^[1]. Ispinesib is a highly specific inhibitor of the kinesin spindle protein (KSP) with a median IC50 value of 5 nM^[2].
  The MDA-MB-468 cells (sensitive to ispinesib) and BT-474 cells(not sensitive to ispinesib) were treated with 150 nmol/L ispinesib and the expression of cell cycle markers (cyclin A, cyclin B and cyclin E) and apoptotic proteins (Bax, Bid, phospho-Bcl2, Bcl2 and Bcl-XL) were analyzed by western blotting at 0, 6, 16 and 48 hours. The expression of proteins Bax and Bid was higher in MDA-MB-468 cells and antiapoptitic protein Bcl-XL was lower. The marker of mitosis cyclin B was increased as the time increased in MDA-MB-468 cells but not in BT-474 cells. The cyclin E also increased after the ispinesib treatment on MDA-MB-468 cells^[3].
  CB17SC-M scid -/- female mice and BALB/c nu/nu mice with tumors xenografts were intraperitoneally administered Ispinesib (5 or 10 mg/kg) every 4 days for 3 doses repeated at day 21. Ispinesib could significantly delay the tumor growth in 88% and had intermediate 21% of solid tumor xenografts^[4].
• 作用机制The ability of KSP to bind to microtubules and the movement is changed and inhibited by ispinesib through preventing ADP release without inhibiting the release of the KSP-ADP complex from the microtubule^[5].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human BxPC3 cells	-	Growth inhibition assay	72 h	Growth inhibition of human BxPC3 cells after 72 hrs by Alamar blue assay, GI50=0.08 μM	23394180
  human BxPC3 cells	-	Proliferation assay	72 h	Antiproliferative activity against human BxPC3 cells after 72 hrs by Alamar blue assay, GI50=0.08 μM	22248262
  human HCT116 cells	-	Growth inhibition assay	72 h	Growth inhibition of human HCT116 cells after 72 hrs by MTS assay, IC50=1.1 nM	26396688

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• 动物研究
  剂量	Mice: 10 mg/kg[3] (i.p.)
  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
  NCT00169520	Solid Tumor Cancer	Phase 1	Completed	-	United Kingdom ... more >> GSK Investigational Site Oxford, Oxfordshire, United Kingdom, OX2 6PD GSK Investigational Site London, United Kingdom, SW3 6JJ Collapse <<
  NCT00607841	Breast Neoplasms	Phase 1 Phase 2	Completed	-	Peru ... more >> Hospital Nacional Alberto Sabogal Sologúren Lima, Peru Hospital Nacional Edgardo Rebagliati Martins Lima, Peru Instituto Nacional de Enfermedades Neoplásicas Lima, Peru Collapse <<
  NCT00103311	-	-	Completed	-	-

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• 参考文献

• [1] Endow SA, Kull FJ, Liu H. Kinesins at a glance. J Cell Sci. 2010;123(Pt 20):3420-4.

  [2] Sheth PR, Basso A, et al. Thermodynamics of nucleotide and inhibitor binding to wild-type and ispinesib-resistant forms of human kinesin spindle protein. Biochemistry. 2009;48(46):11045-55.

  [3] Purcell JW, Davis J, et al. Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer. Clin Cancer Res. 2010;16(2):566-76.

  [4] Carol H, Lock R, et al. Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program. Pediatr Blood Cancer. 2009;53(7):1255-63.

  [5] Lad L, Luo L, et al. Mechanism of inhibition of human KSP by ispinesib. Biochemistry. 2008;47(11):3576-85.

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