Ispinesib (SB-715992)

Ispinesib (SB-715992)は、KSP(HsEg5)のアロステリックで、強力で、特定で、可逆的な阻害剤で、Ki が 1.7 nM。

目録号S1452
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Ispinesib (SB-715992) 化学構造
分子量: 517.06

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Quality Control & MSDS

製品情報

  • Compare Kinesin Inhibitors
    Kinesin阻害剤を比較
  • 研究分野
  • Ispinesib (SB-715992)のメカニズム

製品の説明

生物活性

情報 Ispinesib (SB-715992)は、KSP(HsEg5)のアロステリックで、強力で、特定で、可逆的な阻害剤で、Ki が 1.7 nM。
目標 KSP (HsEg5)
IC50 1.7 nM (Ki app) [1]
In vitro試験 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]
In vivo試験 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. [2] 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]
臨床試験 Investigations of Ispinesib in multiple Phase II clinical trials for several cancers, including kidney, prostate, colorectal, liver, ovarian, and breast cancers, have been completed.
特集 An allosteric, potent, specific, and reversible inhibitor of the mitotic kinesin spindle protein (KSP) (HsEg5).

推薦された実験操作 (公開の文献だけ)

キナーゼアッセイ: [1]

Steady-State Kinetic Analysis of Human KSP ATPase Activity and Inhibition by Ispinesib Kinesin specificity analysis is carried out using a pyruvate kinase-lactate dehydrogenase detection system that couples the production of ADP to oxidation of NADH. Absorbance changes are monitored at 340 nm. Steady-state studies using nanomolar concentrations of KSP are performed using a sensitive fluorescence-based assay utilizing a pyruvate kinase, pyruvate oxidase, and horseradish peroxidase (HRP) coupled detection system that couples the generation of ADP to oxidation of Amplex Red to fluorescent resorufin. Generation of resorufin is monitored by fluorescence (λexcitation = 520 nm and λemission = 580 nm). Steady-state biochemical experiments are performed in PEM25 buffer [25 mM Pipes-K+ (pH 6.8), 2 mM MgCl2, 1 mM EGTA] supplemented with 10 µM paclitaxel for experiments involving microtubules. The IC50 for steady-state inhibition is determined at 500 µM ATP, 5 µM Microtubules, and 1 nM KSP in PEM25 buffer. Ki app (apparent inhibitor dissociation constant) values of Ispinesib are extracted from the dose-response curves, with explicit correction for enzyme concentration by using the Morrison equation. Inhibitor modality (e.g., competitive, noncompetitive, uncompetitive, or mixed) under steady-state conditions is determined by measuring the effect of inhibitor concentration on initial velocity as a function of substrate concentrations. Data are fit using equations in GraFit to velocity equations for the various modes of inhibition.

細胞アッセイ: [4]

細胞系 Breast cancer cells, including MCF-7, HCC1954, MDA-MB-468, and KPL4
濃度 0.085 nM–33 µM
処理時間 72 hours
方法 Cells are plated in log phase of growth in 96-well plates and treated with Ispinesib for 72 hours. Then, cell growth is measured using CellTiter-Glo, and luminescence is detected using BioTek FLx800. Data are analyzed and the IC50 value, defined as the drug concentration that results in 50% growth inhibition relative to control, is calculated.

動物実験: [4]

動物モデル Nude (nu/nu) mice models of MCF7, KPL4, and HCC1954 cells; severe combined immunodeficient (SCID) mice model of MDA-MB-468 cells;
製剤 Dissolved in 10% ethanol, 10% cremophor, and 80% D5W (dextrose 5%)
投薬量 10 mg/kg for nude mice or 8 mg/kg for SCID mice
管理 Intraperitoneal injection on a q4d× schedule (3 doses, every 4 day

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesBaboonDogMonkeyRabbitGuinea pigRatHamsterMouse
Weight (kg)121031.80.40.150.080.02
Body Surface Area (m2)0.60.50.240.150.050.0250.020.007
Km factor202012128653
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.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

参考

化学情報

Download Ispinesib (SB-715992) SDF
分子量 517.06
化学式

C30H33ClN4O2

CAS No. 336113-53-2
保管 2年-20℃
6月-80℃in DMSO
別名 CK0238273
溶解度 (25°C) * In vitro DMSO 103 mg/mL (199 mM)
<1 mg/mL (<1 mM)
エタノール 103 mg/mL (199 mM)
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
化学名 (R)-N-(3-aminopropyl)-N-(1-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methylpropyl)-4-methylbenzamide

研究分野

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Rating
Source , , PLoS One. 2013 Apr 10;8(4):e60334 . Ispinesib (SB-715992) purchased from Selleck
Method Cell imaging-based efflux assay
Cell Lines KB-V1 cells
Concentrations 0-20 uM
Incubation Time 24 h
Results Ispinesib inhibited ABCB1-medicated calcein AM efflux in the flow cytometry assay and displayed dose-dependent inhibition of ABCB1-mediated efflux in our cell imaging-based efflux assay.

Click to enlarge
Rating
Source , , PLoS One. 2013 Apr 10;8(4):e60334 . Ispinesib (SB-715992) purchased from Selleck
Method Flow cytometry-based efflux assays
Cell Lines KB-V1 cells
Concentrations 5 uM
Incubation Time 24 h
Results Flow cytometry-based efflux assays were performed to examine KB-V1 cells incubated with either calcein AM (1 μM, red line) or calcein AM plus BEZ235, BI 2536, IKK 16, ispinesib, or bryostatin-1 (5 μM, blue line).

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