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.
Curr Cancer Drug Targets. 2023;23(4):293-306.
Combined Inhibition of KIF11 and KIF15 as an Effective Therapeutic Strategy for Gastric Cancer
Ispinesib purchased from AbMole
| Cell Experiment | |
|---|---|
| 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 Experiment | |
|---|---|
| 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 |
| Administration | i.p. |
| Molecular Weight | 517.06 |
| Formula | C30H33ClN4O2 |
| CAS Number | 336113-53-2 |
| Solubility (25°C) | DMSO ≥ 60 mg/mL |
| Storage | 2-8°C, protect from light |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
| Related Kinesin Products |
|---|
| Eg5-IN-1
Eg5-IN-1 is a potent kinesin family motor protein (Eg5) inhibitor with an IC50 value of 1.97 µM. |
| PVZB-1194
PVZB-1194 is a biphenyl-type inhibitor of kinesin Eg5 that induces apoptosis by inhibiting Eg5 ATPase activity and shows potent kinesin spindle protein (KSP) inhibition only in the presence of microtubules, with anticancer activity. |
| Litronesib
Litronesib (LY2523355) is a selective mitosis-specific kinesin Eg5 inhibitor, with antitumor activity. |
| MK-0731
MK-0731 is a selective, non-competitive and allosteric kinesin spindle protein (KSP) inhibitor with an IC50 of 2.2 nM and a pKa of 7.6. MK-0731 is >20,000 fold selectivity against other kinesins. MK-0731 induces mitotic arrest and induces apoptosis in tumors. MK-0731 provides significant antitumor efficacy. |
| BRD9876
BRD9876 is the “rigor” inhibitor that locks kinesin-5 (Eg5) in a state with enhanced microtubules (MTs) binding, leading to bundling and stabilization of MTs. BRD9876 interacts with the tyrosine 104 residue that is part of the α4-α6 allosteric binding pocket. BRD9876 specifically targets microtubule-bound Eg5 and selectively inhibits myeloma over CD34 cells. BRD9876 has the potential for multiple myeloma (MM) research. |
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