Ispinesib (SB-715992)

製品コードS1452 バッチS145201

化学情報

	Synonyms	CK0238273	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₃₀H₃₃ClN₄O₂
	分子量	517.06	CAS No.	336113-53-2
Solubility (25°C)*	体外	DMSO	103 mg/mL (199.2 mM)
		Ethanol	103 mg/mL (199.2 mM)
		Water	Insoluble
* <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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	Ispinesib (SB-715992, CK0238273) is a potent, specific and reversible inhibitor of kinesin spindle protein (KSP) with K_{i app} of 1.7 nM in a cell-free assay, no inhibition to CENP-E, RabK6, MCAK, MKLP1, KHC or Kif1A. Ispinesib induces mitotic arrest and apoptotic cell death.
in vitro	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-X_L level, and higher proapoptotic Bax and Bid levels. ^[4]
in vivo	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]
特徴	An allosteric, potent, specific, and reversible inhibitor of the mitotic kinesin spindle protein (KSP) (HsEg5).

プロトコル(参考用のみ)

キナーゼアッセイ	Steady-State Kinetic Analysis of Human KSP ATPase Activity and Inhibition by Ispinesib
キナーゼアッセイ	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 (λ_excitation = 520 nm and λ_emission = 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. K_{i 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	細胞株	Breast cancer cells, including MCF-7, HCC1954, MDA-MB-468, and KPL4
	濃度	0.085 nM–33 µM
	反応時間	72 hours
	実験の流れ	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	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;
	投薬量	10 mg/kg for nude mice or 8 mg/kg for SCID mice
	投与方法	Intraperitoneal injection on a q4d× schedule (3 doses, every 4 day

参考

[4] Purcell JW, et al. Clin Cancer Res, 2010, 16(2), 566-576.

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カスタマーフィードバック

: Data from [Data independently produced by Mol Oncol, 2014, 8(8), 1548-60]

: Data from [Data independently produced by J Biol Chem, 2014, 289(45), 31111-20]

: Data from [PLoS One, 2013, 8(4), e60334]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Small-molecule inhibition of kinesin KIF18A reveals a mitotic vulnerability enriched in chromosomally unstable cancers [ Nat Cancer, 2024, 5(1):66-84]	PubMed: 38151625
E3 ubiquitin ligase ASB8 promotes selinexor-induced proteasomal degradation of XPO1 [ Biomed Pharmacother, 2023, 160:114305]	PubMed: 36731340
Improving Localized Radiotherapy for Glioblastoma via Small Molecule Inhibition of KIF11 [ Cancers (Basel), 2023, 15(12)3173]	PubMed: 37370783
The Global Phosphorylation Landscape of SARS-CoV-2 Infection [ Cell, 2020, 182(3):685-712.e19]	PubMed: 32645325
The Global Phosphorylation Landscape of SARS-CoV-2 Infection [ Cell, 2020, 182(3):685-712.e19]	PubMed: 32645325
Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma [ Sci Transl Med, 2020, 12(562)eaba4434]	PubMed: 32967973
enAsCas12a Enables CRISPR-Directed Evolution to Screen for Functional Drug Resistance Mutations in Sequences Inaccessible to SpCas9 [ Mol Ther, 2020, S1525-0016(20)30482-2]	PubMed: 33002419
Enhancing Brain Retention of a KIF11 Inhibitor Significantly Improves its Efficacy in a Mouse Model of Glioblastoma. [ Sci Rep, 2020, 16;10(1):6524]	PubMed: 32300151
KIF11 and KIF15 mitotic kinesins are potential therapeutic vulnerabilities for malignant peripheral nerve sheath tumors [ Neurooncol Adv, 2020, 2(Suppl 1):i62-i74]	PubMed: 32642733
Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds [ Nature, 2019, 575(7781):203-209]	PubMed: 31666698

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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