Ispinesib

Uses

The kinesin-like spindle protein Eg5 (also known as kinesin-5, kinesin family protein 11, or Kif11) is a motor protein that is essential for establishing a bipolar spindle during mitosis both in normal and tumor cells. Ispinesib is a cell-permeable, allosteric inhibitor of Eg5 (Ki app = 2.3 nM) with >10,000-fold selectivity for Eg5 over a range of other mitotic kinesins. It induces a monopolar spindle phenotype, leading to the activation of a spindle assembly checkpoint, mitotic arrest, and subsequent cell death (GI50s = 22-82 nM in colon, pancreas, prostrate, and lung cancer cells in vitro). At 10 mg/kg, ispinesib produces tumor regression of breast cancer cell xenografts in mice. It has also been used to halt the growth of treatment-resistant glioblastoma tumor-initiating cells, to prevent tumor initiation and self-renewal of a cancer stem cell population (EC50 = 1.15 nM), and to reduce glioma cell invasion.[Cayman Chemical]

Definition

ChEBI: N-(3-aminopropyl)-N-[(1R)-1-[7-chloro-4-oxo-3-(phenylmethyl)-2-quinazolinyl]-2-methylpropyl]-4-methylbenzamide is a member of benzamides.

Biological Activity

ispinesib (sb-715992) is a selective inhibitor of ksp with ic50 value of 0.5 nm [1].kinesin spindle protein (ksp) is a kinesin motor protein and plays an important role in the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. it has been shown that abnormal expression of ksp is correlated with a variety of human cancers and its inhibitors may be a promising anticancer agent [2] [3].ispinesib (sb-715992) is a potent ksp inhibitor and often combines with chemotherapy drugs to tumor treatment. when tested with a panel of 23 tumor cell lines, ispinesib (sb-715992) treatment showed high activity to inhibit ksp in most of the cell lines while only rh18 having an ic50 value greater than 1 μm (median ic50=4.1 nm, maximum ic50=0.5 nm) by using pptp method [1]. in a panel of 53 breast cell lines, ispinesib (sb-715992) exhibits broad antiproliferative activity and up-regulated the expression of both mitotic and apoptotic markers in mda-mb-468 cell line [2]. when tested with pc-3 cells, ispinesib (sb-715992) treatment inhibits cell proliferation, inducs cell apoptosis and up-regulated the expressions of genes that related to the control of cell proliferation, cell cycle, cell signaling pathways and apoptosis [3].in mouse model with 26 tumor cells subcutaneous xenograft, administration of ispinesib (sb-715992) inducs markedly tumor growth delay with the percent of 88% (23/26) and maintained completed response (cr) in the rhaboid tumor, wilms tumor and ewing sarcoma xenograft mouse model [1].

in vivo

IC 50

KSP: 1.7 nM (Ki app)

storage

Store at -20°C

References

[1]. carol, h., 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): p. 1255-63.
[2]. purcell, j.w., et al., activity of the kinesin spindle protein inhibitor ispinesib (sb-715992) in models of breast cancer. clin cancer res, 2010. 16(2): p. 566-76.
[3]. davis, d.a., et al., increased therapeutic potential of an experimental anti-mitotic inhibitor sb715992 by genistein in pc-3 human prostate cancer cell line. bmc cancer, 2006. 6: p. 22.