Tozasertib (VX-680)

製品コードS1048 バッチS104804

印刷

化学情報

Chemical Structure Synonyms MK-0457 Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C23H28N8OS
分子量 464.59 CAS No. 639089-54-6
Solubility (25°C)* 体外 DMSO 93 mg/mL (200.17 mM)
Water Insoluble
Ethanol Insoluble
体内 （毎回新しく調製した物を用意してください）
Homogeneous suspension
CMC-NA
≥5mg/ml Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
* <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 Tozasertib (VX-680)は、Aurora Aに対するKiappがセルフリーアッセイで0.6 nMのパンAurora阻害剤であり、Aurora B/Aurora Cに対する効力は低く、他の55のキナーゼよりもAurora Aに対して100倍選択的です。唯一の例外は、Kiが30 nMでTozasertibによって阻害されるFms-related tyrosine kinase-3 (FLT-3)とBCR-ABL tyrosine kinaseです。Tozasertibはapoptosisとautophagyを誘導します。フェーズ2。
in vitro Although its multi-kinase profile, Tozasertib (VX-680) induces similar cytotoxicity with IC50 of approximately 300 nM and exhibits an AUR B-like inhibitory phenotype of G2/M arrest, endoreduplication and apoptosis in BaF3 cells transfected with ABL or FLT-3 (mutant and wild type) kinases. This compound prevents the CAL-62 proliferation in a time-dependent manner. Treatment for 14 days significantly decreases the number and size of colonies by approximately 70% in the 8305C and 90% in the CAL-62, 8505C and BHT-101. Treatment of the different ATC cells with it inhibits proliferation with the IC50 between 25 and 150 nM. It significantly impairs the ability of the different cell lines to form colonies in soft agar. Analysis of caspase-3 activity indicates that VX-680 induces apoptosis in the different cell lines. CAL-62 cells exposed for 12  hours to the compound showed an accumulation of cells with ≥4N DNA content. Time-lapse analysis demonstrates that treated CAL-62 cells exit metaphase without dividing. Moreover, histone H3 phosphorylation is abrogated following its treatment. It has significant inhibitory activity against BCR-Abl bearing the T315I mutation in patient-derived samples.
in vivo Tozasertib (VX-680) gives rise to a marked decrease in tumor size in a human AML (HL-60) xenograft model. In mude mice treateed with it at 75 mg/kg, twice a day intraperitoneally (b.i.d. i.p.) for 13 days, mean tumor volumes are reduced by 98%. Tumor growth decrease is dose dependent and significant at a dose of 12.5 mg/kg b.i.d. This compound is well tolerated, with a small decrease in body weight observed only at the highest dose. It also triggers tumor regresson in pancreatic and colon xenograft models. Tozasertib also displays potent antitumor activity when infused i.v. in mude rats bearing established HCT116 tumors. A higher dose (2 mg/kg/h) improves efficacy with a 56% decrease in mean tumor volume.

プロトコル(参考用のみ)

キナーゼアッセイ Kinase inhibition assays
The consumption of ATP is coupled via the pyruvate kinase/lactic dehydrogenase enzyme pair to the oxidation of NADH, which can be monitored through the decrease in absorption at 340 nm. Reactions contains 100 mM Tris (pH 8), 10 mM MgCl2, 2.2 mM ATP, 1 mM phosphoenolpyruvate, 0.6 mg/mL NADH, 75 units/mL pyruvate kinase, 105 units/mL lactate dehydrogenase, and 0.5 mM substrate peptide (sequence: EAIYAAPFAKKK). Reactions (75 μL) are started by adding sufficient kinase to bring the reactions to 30 nM kinase concentration and the decrease in absorbance is monitored over 30 minutes at 30°C in a microtiter plate spectrophotometer. Inhibitory constants are obtained through addition of 3.75 μL Tozasertib (VX-680) in 100% DMSO or DMSO alone. Ki values are calculated as follows, K i = IC50 / (1 + [S]/Kd), where [S] = [ATP] = 2.2 mM, and Kd (of ATP to Abl) = 70 μM. These values are calculated assuming a Kd (ATP) of 70 μM for wild type and H396P Abl kinase domain.
細胞アッセイ 細胞株 CAL-62 cells
濃度 5-500 nM
反応時間 4 days
実験の流れ

The CAL-62 cells are cultured in the absence (dimethyl sulfoxide, DMSO) or the presence of 500  nM Tozasertib (VX-680) for different periods of time (1-5 days). The dose-dependent effects of this compound on cell proliferation are evaluated by treating the different ATC cells for 4 days with different concentrations of the Aurora inhibitor (5–500  nM). The cells are pulse labeled with 30  mM BrdU for 2  hours before the end of the incubation time. The BrdU incorporation is analyzed by means of a colorimetric immunoassay using the cell proliferation ELISA kit. The results from VX-680-treated cells are compared with those observed in control cells and expressed as a fold of variation versus control.
動物実験 動物モデル Female athymic NCr-nu mice bearing HL-60 leukemia cells
投薬量 50 mg/kg, 75 mg/kg
投与方法 Administered via i.p.

参考

  • https://pubmed.ncbi.nlm.nih.gov/14981513/
  • https://pubmed.ncbi.nlm.nih.gov/18430894/
  • https://pubmed.ncbi.nlm.nih.gov/16424036/
  • https://pubmed.ncbi.nlm.nih.gov/17240048/

カスタマーフィードバック

Data from [Oncogene, 2012, 31, 3584-96]

Data from [Oncogene, 2012, 31, 3584-96]

Data from [Brain Pathol, 2012, 23, 244-53]

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：

A patient-derived T cell lymphoma biorepository uncovers pathogenetic mechanisms and host-related therapeutic vulnerabilities [ Cell Rep Med, 2025, S2666-3791(25)00102-8] PubMed: 40147445
Overcoming MET-targeted drug resistance in MET-amplified lung cancer by aurora kinase B inhibition [ Biochim Biophys Acta Mol Cell Res, 2025, 1872(7):120001] PubMed: 40499687
Hedgehog signalling is involved in acquired resistance to KRASG12C inhibitors in lung cancer cells [ Cell Death Dis, 2024, 15(1):56] PubMed: 38225225
Dynamic phosphorylation of FOXA1 by Aurora B guides post-mitotic gene reactivation [ Cell Rep, 2024, 43(9):114739] PubMed: 39276350
The molecular basis of Abelson kinase regulation by its αI-helix [ Elife, 2024, 12RP92324] PubMed: 38588001
Tozasertib activates anti-tumor immunity through decreasing regulatory T cells in melanoma [ Neoplasia, 2024, 48:100966] PubMed: 38237304
Machine learning based androgen receptor regulatory gene-related random forest survival model for precise treatment decision in prostate cancer [ Heliyon, 2024, 10(17):e37256] PubMed: 39296076
Visualization strategies to aid interpretation of high-dimensional genotoxicity data [ Environ Mol Mutagen, 2024, 10.1002/em.22604] PubMed: 38757760
Molecular landscape and functional characterization of centrosome amplification in ovarian cancer [ Nat Commun, 2023, 14(1):6505] PubMed: 37845213
Mitotic Dysregulation at Tumor Initiation Creates a Therapeutic Vulnerability to Combination Anti-Mitotic and Pro-Apoptotic Agents for MYCN-Driven Neuroblastoma [ Int J Mol Sci, 2023, 10.3390/ijms242115571] PubMed: 37958555

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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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