Ispinesib (SB-715992), a potent and selective small molecule inhibitor of KSP, functions by inhibiting KSP ATPase and is 40000 times more selective for KSP compared to other kinesins. In preclinical studies, ispinesib inhibited growth in a wide range of human and murine cell lines with IC50 values of 1.2-9.5nm. Treatment of SKOV3 ovarian tumour cells in vitro with 20nm of ispinesib, or a Colo 205 colon cancer murine xenograft model with 30mgkg-1 of intraperitoneal ispinesib, caused mitotic arrest with cells demonstrating unseparated centrosomes and monopolar mitotic spindles. Tumour growth delay was observed in xenograft models of colon (HT29, Colo201, Colo205), non-small cell lung (Calu-3) and pancreatic (Panc-01) cancers.
|Cell lines||BT-474 and MDA-MB-468 cells line|
|Preparation method||Cell lines were obtained from the American Type Culture Collection and from collections developed by Drs. Steve Ethier and Adi Gazdar. KPL4 was kindly provided by Dr J. Kurebayashi (Kawasaki Medical School, Kurashiki, Okayama, Japan). Cell culture reagents were from Cellgro-Mediatech. Cells were plated in log phase of growth in 96-well plates and treated for 72 h with ispinesib at concentrations of 3.3 × 10−5 to 8.5 × 10−11 mol/L. Cell growth was measured using CellTiter-Glo (Promega), and luminescence was recorded using BioTek FLx800. Data were analyzed according to the method described previously by the National Cancer Institute/NIH Developmental Therapeutics Program Human Tumor Cell Line Screen Process. The GI50 value is the drug concentration that results in 50% growth inhibition after 72 h of drug exposure relative to control.|
|Concentrations||0~1000 n M|
|Incubation time||72 h|
|Animal models||MCF-7, BT-474 and MDA-MB-468 xenograft model in nude mice or SCID mice|
|Formulation||formulated in 10% ethanol, 10% cremophor, and 80% D5W (dextrose 5%)|
|Dosages||q4d×3 schedule at 10 mg/kg in nu/nu mice or 8 mg/kg in SCID mice|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer.
Purcell et al. Clin Cancer Res. 2010 Jan 15;16(2):566-76. PMID: 20068098.
Thermodynamics of nucleotide and inhibitor binding to wild-type and ispinesib-resistant forms of human kinesin spindle protein.
Sheth et al. Biochemistry. 2009 Nov 24;48(46):11045-55. PMID: 19824700.
|Related Kinesin Products|
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EMD534085 is a potent and selective inhibitor of the mitotic kinesin-5 with an IC50 of 8 nM.
BAY 1217389 is a potent, and selective inhibitor of the monopolar spindle 1 (MPS1) kinase with an IC50 value less than 10 nM.
Monastrol is a cell-permeable small molecule inhibitor of kinesin-5(KIF11) which is essential for maintaining separation of the half-spindles.
AZD4877 is a synthetic kinesin spindle protein (KSP) inhibitor with potential antineoplastic activity.
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