Abexinostat (PCI-24781)

製品コードS1090 バッチS109005

印刷

化学情報

Synonyms

CRA-024781

Storage
(From the date of receipt)

3 years -20°C powder
1 years -80°C in solvent

化学式

C₂₁H₂₃N₃O₅

分子量

397.42

CAS No.

783355-60-2

Solubility (25°C)*

体外

DMSO

5 mg/mL (12.58 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.
Clear solution	5%DMSO 1 40%PEG300 2 5%Tween80 3 50%ddH2O この製剤はselleckのラボで検証済みです。上記の溶解方法がご要望を満たさない場合、selleckの営業担当までお問い合わせ頂ければ、個別の試験を行います。	0.250mg/ml (0.63mM)	Taking the 1 mL working solution as an example, add 50 μL of 5 mg/ml clarified DMSO stock solution to 400 μL of PEG300, mix evenly to clarify it; add 50 μL of Tween80 to the above system, mix evenly to clarify; then continue to add 500 μL of ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.
Clear solution	5% DMSO 1 95% Corn oil この製剤はselleckのラボで検証済みです。上記の溶解方法がご要望を満たさない場合、selleckの営業担当までお問い合わせ頂ければ、個別の試験を行います。	0.250mg/ml (0.63mM)	Taking the 1 mL working solution as an example, add 50 μL of 5 mg/ml clear DMSO stock solution to 950 μL of corn oil and mix evenly. The mixed solution should be used immediately for optimal results.

* <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	Abexinostat (PCI-24781, CRA-024781) は、主にHDAC1 をターゲットとする新規の pan-HDAC 阻害剤で、K_i は 7 nM です。HDACs 2、3、6、および 10 に対して中程度の効力を持ち、HDAC8 に対しては 40 倍以上の選択性があります。第 1/2 相。
in vitro	Abexinostat (PCI-24781) exhibits potent antitumor activity against a variety of tumor cell lines with GI50 ranging from 0.15 μM to 3.09 μM, and also has an antiproliferative effect on HUVEC endothelial cells with GI50 of 0.43 μM. Treatment with this compound causes dose-dependent accumulation of both acetylated histones and acetylated tubulin in HCT116 or DLD-1 cells, induces expression of p21, and leads to PARP cleavage and accumulation of the γH2AX. Inhibition of HDAC enzymes by PCI-24781 leads to a significant reduction in the transcription of genes specifically associated with HR, including RAD51. Consistent with inhibition of HR, it results in a decreased ability to perform homology directed repair of I-SceI-induced chromosome breaks in transfected CHO cells. It induces S phase depletion, G2 cell cycle arrest, and apoptosis in soft tissue sarcoma (STS) cells, and also causes Rad51 transcriptional repression in STS cells potentially mediated via enhanced E2F1 binding to the Rad51 proximal promoter. Additionally, this compound induces caspase and reactive oxygen species-dependent apoptosis through NF-κB mechanisms in Hodgkin lymphoma and non-Hodgkin lymphoma cell lines.
in vivo	Abexinostat (PCI-24781) was administered at 200 mg/kg once daily every other day (q.o.d.), which significantly inhibited the growth of HCT116 and DLD-1 xenografts in mice by 69% and 59%, respectively. In the HCT116 model, administration of this compound at 20 mg/kg, 40 mg/kg, 80 mg/kg, or 160 mg/kg once daily for 4 consecutive days followed by 3 days without treatment each week (q.d. × 4 per week) caused inhibition of tumor growth by 48%, 57%, 82.2%, or 80.0%, respectively.

プロトコル(参考用のみ)

キナーゼアッセイ	HDAC Activity
キナーゼアッセイ	HDAC activity is measured using a continuous trypsin-coupled assay. For inhibitor characterization, measurements are done in a reaction volume of 100 μL using 96-well assay plates. For each isozyme, the HDAC protein in reaction buffer [50 mM HEPES, 100 mM KCl, 0.001% Tween 20, 5% DMSO (pH 7.4), supplemented with bovine serum albumin at concentrations of 0% (HDAC1), 0.01% (HDAC2, 3, 8, and 10), or 0.05% (HDAC6)] is mixed with Abexinostat (PCI-24781) at various concentrations and allowed to incubate for 15 minutes. Trypsin is added to a final concentration of 50 nM, and acetyl-Gly-Ala-(N-acetyl-Lys)-AMC is added to a final concentration of 25 μM (HDAC1, 3, and 6), 50 μM (HDAC2 and 10), or 100 μM (HDAC8) to initiate the reaction. Negative control reactions are done in the absence of this compound in replicates of eight. Reactions are monitored in a fluorescence plate reader. After a 30-minute lag time, the fluorescence is measured over a 30-minute time frame using an excitation wavelength of 355 nm and a detection wavelength of 460 nm. The increase in fluorescence with time is used as the measure of the reaction rate. Inhibition constants K_i(app) are obtained using the program BatchKi.
細胞アッセイ	細胞株	HCT116, HCT-15, BT-549, NCI-H226, CWR-22RV1, MCF-7, NCI-PC3, DLD-1, SKOV-3, and OVCAR-3
	濃度	Dissolved in DMSO, final concentrations ~10 μM
	反応時間	48, 72, 96, or 120 hours
	実験の流れ	Cells are cultured for at least two doubling times, and growth is monitored at the end of exposure to Abexinostat (PCI-24781) using an Alamar blue fluorometric cell proliferation assay. This compound is assayed in triplicate wells in 96-well plates at nine concentrations using half-log intervals ranging from 0.0015 μM to 10 μM. The final DMSO concentration in each well is 0.15%. The concentration required to inhibit cell growth by 50% (GI50) and 95% confidence intervals are estimated from nonlinear regression using a four-parameter logistic equation.
動物実験	動物モデル	Female BALB/c nu/nu mice implanted s.c. with HCT116 and DLD-1 tumor cells
	投薬量	~200 mg/kg
	投与方法	Administered via i.v.

参考

https://pubmed.ncbi.nlm.nih.gov/16731764/
https://pubmed.ncbi.nlm.nih.gov/18042714/
https://pubmed.ncbi.nlm.nih.gov/19417021/

https://pubmed.ncbi.nlm.nih.gov/19417023/

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カスタマーフィードバック

: Data from [Biochem Bioph Res Co, 2012, 55, 2421-31]

: Data from [Nat Biotechnol, 2011, 29, 255-265]

: Data from [Biochem Bioph Res Co, 2011, 414, 25-30]

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：

Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma [ Nat Biomed Eng, 2024, 10.1038/s41551-024-01273-9]	PubMed: 39658630
Deciphering the Metabolic Basis and Molecular Circuitry of the Warburg Paradox in Lymphoma [ Cancers (Basel), 2024, 16(21)3606]	PubMed: 39518046
Nuclear oligo hashing improves differential analysis of single-cell RNA-seq [ Nat Commun, 2022, 13(1):2666]	PubMed: 35562344
Single-cell profiling-guided combination therapy of c-Fos and histone deacetylase inhibitors in diffuse large B-cell lymphoma [ Clin Transl Med, 2022, 12(5):e798]	PubMed: 35522945
Small-molecule inhibitors of histone deacetylase improve CRISPR-based adenine base editing [ Nucleic Acids Res, 2021, 49(4):2390-2399]	PubMed: 33544854
Epigenetic targeting of the ACE2 and NRP1 viral receptors limits SARS-CoV-2 infectivity [ Clin Epigenetics, 2021, 13(1):187]	PubMed: 34635175
Combining APR-246 and HDAC-Inhibitors: A Novel Targeted Treatment Option for Neuroblastoma [ Cancers (Basel), 2021, 13(17)4476]	PubMed: 34503286
Quantifying Drug Combination Synergy along Potency and Efficacy Axes. [ Cell Syst, 2019, 8(2):97-108]	PubMed: 30797775
Epigenetic Reprogramming with Antisense Oligonucleotides Enhances the Effectiveness of Androgen Receptor Inhibition in Castration-Resistant Prostate Cancer [ Cancer Res, 2018, 78(20):5731-5740]	PubMed: 30135193
Dual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance. [ Sci Rep, 2018, 8(1):10039]	PubMed: 29968769

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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