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AR-42 HDAC inhibitor

Cat.No.S2244

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

Chemical Structure

Molecular Weight: 312.36

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Chemical Information, Storage & Stability

Molecular Weight 312.36 Formula

C18H20N2O3

 Storage (From the date of receipt)
CAS No. 935881-37-1 Download SDF Storage of Stock Solutions

Synonyms HDAC-42 Smiles CC(C)C(C1=CC=CC=C1)C(=O)NC2=CC=C(C=C2)C(=O)NO

Solubility

In vitro
Batch:

DMSO : 63 mg/mL ( (201.69 mM) Moisture-absorbing DMSO reduces solubility. Please use fresh DMSO.)

Ethanol : 63 mg/mL

Water : Insoluble

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In vivo
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Mechanism of Action

Features
Greater potency relative to SAHA.
Targets/IC50/Ki
HDAC [1]
(Cell-free assay)
30 nM
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.
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]
References
  • 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/

Applications

Methods Biomarkers Images 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 20824695
Growth inhibition assay Cell viability S2244-viability1 26993777

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

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

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