GSK923295

製品コードS7090 バッチS709001

印刷

化学情報

Chemical Structure Synonyms N/A Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C32H38ClN5O4
分子量 592.13 CAS No. 1088965-37-0
Solubility (25°C)* 体外 DMSO 100 mg/mL (168.88 mM)
Ethanol 100 mg/mL (168.88 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 GSK923295 is a first-in-class, specific allosteric inhibitor of CENP-E kinesin motor ATPase with Ki of 3.2 nM, and less potent to mutant I182 and T183. GSK923295 induces post-mitotic apoptosis. Phase 1.
in vitro GSK923295 is the first potent and selective inhibitor of the mitotic kinesin centromere-associated protein-E (CENP-E). [1][2] GSK923295 is uncompetitive with both ATP and microtubules (MT), inhibiting CENP-E MT-stimulated ATPase activity with a Ki of 3.2 nM, highly selective over other kinesins. GSK923295 inhibits release of inorganic phosphate and stabilizes CENP-E motor domain interaction with microtubules, reduces the rate of ATP-promoted dissociation of CENP-E from MT (koff, MT) by more than 50-fold. GSK923295 causes failure of metaphase chromosome alignment and induces mitotic arrest. GSK923295 is a potent inhibitor of tumor cell growth, with an average GI50 of 253 nM and a median GI50 of 32 nM for 237 tumor cell lines. [1] GSK923295 inhibits tumor cell growth more effectively when mitogen-activated protein kinase (MEK/ERK) signaling is also inhibited. [4]
in vivo GSK923295 produces clear increases in the abundance of mitotic figures and scattered apoptotic bodies in tumors. GSK923295 causes a dose-dependent increase in the ratio of 4n to 2n nuclei. GSK923295 exhibits robust, dose-dependent antitumor activity against Colo205 xenografts, including partial and complete regressions at the 125 mg/kg dose.[1] GSK923295 demonstrates significant antitumor activity against solid tumor models, inducing CRs in Ewing sarcoma, rhabdoid, and rhabdomyosarcoma xenografts, may be a valuable therapeutic target in pediatric cancer. [3]
特徴 First potent, CENP-E-selective inhibitor that has been tested in Phase I clinical trials for treatment of Refractory Cancers.

プロトコル(参考用のみ)

キナーゼアッセイ Enzymology
Kinesin motor domains are expressed in Escherichia coli BL21(DE3) and purified. CENP-E proteins includes residues 2–340 with a carboxyl-terminal 6-his tag. All studies using MT are conducted in PEM25 buffer [25mM PipesK+ (pH 6.8), 2mM MgCl2, 1mM EGTA] supplemented with 10 μM paclitaxel. The IC50 for steady-state inhibition is determined at 500 μM ATP, 5 μM MT, and 1 nM CENP-E in PEM25 buffer.
細胞アッセイ 細胞株 Tumor cell lines
濃度 ~10 μM
反応時間 72 h
実験の流れ Cell-growth inhibition assays are performed by MDS in 384-well plates, and DNA content of fixed cells stained with DAPI using an Incell 1000 is analyzed. DNA content is determined 24 h after seeding (T0) and after exposure to varying concentrations of drug for an additional 72 h (T72). All T72 measurements are normalized to T0. Curves are analyzed using the XLfit curve-fitting tool to determine the concentration of GSK923295 yielding 50% growth inhibition relative to T0 and Ymax values (GI50).
動物実験 動物モデル mice bearing xenografts of the Colo205 colon tumor-cell line
投薬量 125 mg/kg, two cycles of three daily injections separated by 1 week
投与方法 i.p.

カスタマーフィードバック

, , Nat Chem Biol, 2016, 12(4):226-32.

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
A conserved CENP-E region mediates BubR1-independent recruitment to the outer corona at mitotic onset [ Curr Biol, 2024, 34(5):1133-1141.e4] PubMed: 38354735
A farnesyl-dependent structural role for CENP-E in expansion of the fibrous corona [ J Cell Biol, 2024, 223(1)e202303007] PubMed: 37934467
Epigenetic dysregulation from chromosomal transit in micronuclei [ Nature, 2023, 619(7968):176-183] PubMed: 37286593
Epigenetic dysregulation from chromosomal transit in micronuclei [ Nature, 2023, 619(7968):176-183] PubMed: 37286593
Molecular landscape and functional characterization of centrosome amplification in ovarian cancer [ Nat Commun, 2023, 14(1):6505] PubMed: 37845213
ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE [ Cell Death Dis, 2023, 14(7):456] PubMed: 37479754
α-Tubulin detyrosination links the suppression of MCAK activity with taxol cytotoxicity [ J Cell Biol, 2023, 222(2)e202205092] PubMed: 36459065
Tetraploidy-linked sensitization to CENP-E inhibition in human cells [ Mol Oncol, 2023, 17(6):1148-1166] PubMed: 36688680
3D Ultrastructural Visualization of Mitosis Fidelity in Human Cells Using Serial Block Face Scanning Electron Microscopy (SBF-SEM) [ Bio Protoc, 2023, 13(13):e4708] PubMed: 37449034

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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