Ispinesib is a specific inhibitor of KSP, with a Ki app of 1.7 nM.
Description :
A potent, selective, cell-permeable, allosteric inhibitor of Eg5 (mitotic kinesin KSP) with Ki of 2.3 nM; displays >10,000-fold selectivity for Eg5 over a range of other mitotic kinesins; induces a monopolar spindle phenotype, leading to the activation of a spindle assembly checkpoint, mitotic arrest, and subsequent cell death with GI50 of 20-80 nM in colon, pancreas, prostrate, and lung cancer cells; demonstrates tumor regression of breast cancer cell xenografts in mice at 10 mg/kg.
Breast Cancer
Ispinesib is a potent, allosteric, reversible, and specific inhibitor of KSP, which changes the binding property of KSP to microtubules and disturbs its movement by inhibiting ADP release without altering the release of the KSP-ADP complex from the microtubule. [1] Ispinesib shows potent cytotoxic activity in a panel of tumor cell lines, including Colo205, Colo201, HT-29, M5076, Madison-109, and MX-1, with IC50 of 1.2 nM to 9.5 nM. [2] In PC-3 prostate cancer cells, Ispinesib (15 nM and 30 nM) blocks cell proliferation and induces apoptosis by regulating the expression levels of genes that controls apoptosis, cell proliferation, cell cycle, and cell signaling, such as EGFR, p27, p15, and IL-11. [3] In a panel of 53 breast cell lines, Ispinesib (7.4 nM–600 nM) demonstrates broad inhibitory activity. In BT-474 and MDA-MB-468 cells, Ispinesib (150 nM) induces apoptosis, as revealed by a higher proportion of apoptotic cells, lower antiapoptotic Bcl-XL level, and higher proapoptotic Bax and Bid levels. [4]Ispinesib (150 nM) inhibits BT-474 and MDA-MB-468 cell lines, with GI50s of 45 and 19 nM, respectively[5]. Ispinesib (SB715992, 15 and 30 nM) suppresses the proliferation of PC-3 prostate cancer cell by 48.65% and 52.16%, and induces apoptosis of prostate cancer cell by 1094.88% and 1516.70%, respectively. Ispinesib up regulates genes responsible for apoptosis and cell cycle arrest, and down regulates genes responsible for cell proliferation and survival. The anti-proliferation and pro-apoptotic activities of Ispinesib can be enhanced by genistein[6].
Ispinesib (SCID, 8 mg/kg; nude, 10 mg/kg, q4d × 3) reduces tumor volume in mice bearing tumor xenografts of ER-positive (MCF7), HER2-positive (KPL4, HCC1954, and BT-474), and triple-negative (MDA-MB-468) breast cancer cells via i.p. one dose every 4 days repeated three times[2]. Ispinesib (4.5 mg/kg–15 mg/kg) exhibits inhibitory effects against Colo205, Colo201, HT-29, but not MX-1 cells, in mouse xenograft models. SB-715992 (6 mg/kg–10 mg/kg ) also inhibits murine solid tumors, including Madison 109 lung carcinoma, M5076 sarcoma, as well as L1210 and P388 leukemias. [3] In mice xenograft models of breast cancer cells MCF-7, HCC1954, MDA-MB-468, and KPL4, Ispinesib (8 mg/kg–10 mg/kg) inhibits tumor growth. [4]