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AR-42

別名：HDAC-42

AR-42 (HDAC-42) is an HDAC inhibitor with IC50 of 30 nM. Phase 1.

AR-42化学構造

CAS No. 935881-37-1

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AR-42関連製品

シグナル伝達経路

HDAC Signaling Pathways

HDACシグナル伝達経路

HDAC阻害剤の選択性比較

生物活性

製品説明 AR-42 (HDAC-42) is an HDAC inhibitor with IC50 of 30 nM. Phase 1.
特性 Greater potency relative to SAHA.
Targets
HDAC [1]
(Cell-free assay)
30 nM
In Vitro
In vitro AR-42 treatment induces histone hyperacetylation and p21WAF/CIP1 overexpression, and inhibits the growth of DU-145 cells with IC50 of 0.11 μM. [1] This compound is potent in suppressing the proliferation of U87MG and PC-3 cells, in part, because of its ability to down-regulate Akt signaling. [2] It inhibits the growth of PC-3 and LNCaP cells with IC50 of 0.48 μM and 0.3 μM, respectively. Compared to SAHA, this chemical exhibits distinctly superior apoptogenic potency, and causes markedly greater decreases in phospho-Akt, Bcl-xL, and survivin in PC-3 cells. [3] This compound treatment induces growth inhibition, cell- cycle arrest, apoptosis, and activation of caspases-3/7 in malignant mast cell lines. It induces down-regulation of Kit via inhibition of Kit transcription, disassociation between Kit and heat shock protein 90 (HSP90), and up-regulation of HSP70. This treatment down-regulates the expression of p-Akt, total Akt, phosphorylated STAT3/5 (pSTAT3/5), and total STAT3/5. [6] It potently inhibits the growth of JeKo-1, Raji, and 697 cells with IC50 of <0.61 μM. This compound also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. [7] This treatment also induces autophagy through downregulation of Akt/mTOR signaling and inducing ER stress in hepatocellular carcinoma (HCC) cells. [8]
Kinase Assay In vitro HDAC assay
HDAC activity is analyzed by using an HDAC assay kit. This assay is based on the ability of DU-145 nuclear extract, which is rich in HDAC activity, to mediate the deacetylation of the biotinylated [3H]-acetyl histone H4 peptide that is bound to streptavidin agarose beads. The release of [3H]-acetate into the supernatant is measured to calculate the HDAC activity. Sodium butyrate (0.25-1 mM) is used as a positive control.
細胞実験 細胞株 DU-145
濃度 Dissolved in DMSO, final concentrations ~2.5 μM
反応時間 96 hours
実験の流れ

Cells are exposed to varous concentrations of AR-42 for 96 hours. The medium is removed and replaced by 150 μL of 0.5 mg/mL of MTT in RPMI 1640 medium, and the cells are incubated in the CO2 incubator at 37 °C for 2 hours. Supernatants are removed from the wells, and the reduced MTT dye is solubilized with 200 μL/well of DMSO. Absorbance is determined on a plate reader at 570 nm.
実験結果図 Methods Biomarkers 結果図 PMID
Western blot gp130 / p-STAT3 / STAT3 / p-AKT / AKT / p-MEK / MEK Cyclin D1 / p21 / p16 / Cyclin A / Cyclin B1 Act-H3 / Act-H3 / Act-tubulin p-Kit / Kit Notch1 / NICD / Nestin / Zeb-1 / BMI-1 S2244-WB1.gif 20824695
Growth inhibition assay Cell viability S2244-viability1.gif 26993777
In Vivo
In Vivo The growth of PC-3 tumor xenografts is suppressed by 52% and 67% after treatment with AR-42 at 25 mg/kg and 50 mg/kg, respectively, whereas SAHA at 50 mg/kg suppresses growth by 31%. In contrast to mice treated with SAHA, intratumoral levels of phospho-Akt and Bcl-xL are markedly reduced in this compound treated mice. [3] In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, administration of this chemical not only decreases the severity of prostatic intraepithelial neoplasia (PIN) and completely prevents its progression to poorly differentiated carcinoma, but also shifts tumorigenesis to a more differentiated phenotype, suppressing absolute and relative urogenital tract weights by 86% and 85%, respectively. [5] This agent significantly reduces leukocyte counts, and prolongs survival in three separate mouse models of B-cell malignancy without evidence of toxicity. [7]
動物実験 動物モデル Intact male NCr athymic nude mice inoculated s.c. with PC-3 cells
投与量 ~50 mg/kg/day
投与経路 Orally
NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT02795819 Terminated
Renal Cell Carcinoma|Soft Tissue Sarcoma|Metastatic Disease
Virginia Commonwealth University|National Cancer Institute (NCI)
 July 8 2016 Phase 1
NCT02282917 Terminated
Vestibular Schwannoma|Meningioma|Acoustic Neuroma|Neurofibromatosis Type 2
Massachusetts Eye and Ear Infirmary|Johns Hopkins University|Mayo Clinic|Stanford University|Ohio State University|Nationwide Children''s Hospital
 December 2015 Early Phase 1
  • https://pubmed.ncbi.nlm.nih.gov/16107152/
  • https://pubmed.ncbi.nlm.nih.gov/16186112/
  • https://pubmed.ncbi.nlm.nih.gov/16951239/
  • https://pubmed.ncbi.nlm.nih.gov/17545612/
  • https://pubmed.ncbi.nlm.nih.gov/18483287/
  • https://pubmed.ncbi.nlm.nih.gov/20233974/
  • https://pubmed.ncbi.nlm.nih.gov/20532179/
  • https://pubmed.ncbi.nlm.nih.gov/20962572/

化学情報

分子量 312.36 化学式

C18H20N2O3
CAS No. 935881-37-1 SDF Download AR-42 SDFをダウンロードする
Smiles CC(C)C(C1=CC=CC=C1)C(=O)NC2=CC=C(C=C2)C(=O)NO
保管

In vitro
Batch:

DMSO : 63 mg/mL ( (201.69 mM)； 吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Ethanol : 63 mg/mL

Water : Insoluble

モル濃度計算器

in vivo
Batch:

Add solvents to the product individually and in order.

投与溶液組成計算機

実験計算

モル濃度計算器

質量 濃度 体積 分子量

投与溶液組成計算機(クリア溶液)

ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）

mg/kg g μL 匹

ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）

% DMSO % % Tween 80 % ddH2O
%DMSO %

計算結果：

投与溶媒濃度： mg/ml;

DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH2O，を加え完全に溶解させます。

投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。

注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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