AR-42 (HDAC-42, NSC-736012, OSU-42) 935881-37-1_HDAC_DNA Damage_Signaling Pathways_Products

AR-42 (HDAC-42, NSC-736012, OSU-42 etc.) is a novel and potent histone deacetylase (HDAC) inhibitor with potential antitumor activity. At 30 nM, its IC50 inhibits HDAC. It exhibits strong in vivo antitumor efficacy against a variety of tumor types, including hepatic and prostate cancers, as well as strong anti-proliferative activity against different cancer cell lines.

Physicochemical Properties

Molecular Formula

C18H20N2O3

Molecular Weight

312.36

Exact Mass

312.147

Elemental Analysis

C, 69.21; H, 6.45; N, 8.97; O, 15.37

CAS #

935881-37-1

Related CAS #

935881-37-1

PubChem CID

6918848

Appearance

White to light brown solid powder

Density

1.223

LogP

3.647

Hydrogen Bond Donor Count

Hydrogen Bond Acceptor Count

Rotatable Bond Count

Heavy Atom Count

Complexity

397

Defined Atom Stereocenter Count

SMILES

[C@@H](C1C=CC=CC=1)(C(C)C)C(=O)NC1C=CC(C(=O)NO)=CC=1

InChi Key

LAMIXXKAWNLXOC-INIZCTEOSA-N

InChi Code

InChI=1S/C18H20N2O3/c1-12(2)16(13-6-4-3-5-7-13)18(22)19-15-10-8-14(9-11-15)17(21)20-23/h3-12,16,23H,1-2H3,(H,19,22)(H,20,21)/t16-/m0/s1

Chemical Name

N-hydroxy-4-[[(2S)-3-methyl-2-phenylbutanoyl]amino]benzamide

Synonyms

HDAC-42; AR42; AR 42; AR-42; (S)-HDAC-42; AR-42; NSC-736012; OSU-42; OSU 42; OSU42; OSU-HDAC-42; OSU HDAC-42; OSU HDAC 42; OSUHDAC-42

HS Tariff Code

2934.99.9001

Storage

Powder-20°C 3 years

4°C 2 years

In solvent -80°C 6 months

-20°C 1 month

Shipping Condition

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets

HDAC ( IC50 = 16 nM )

ln Vitro

In vitro activity: AR-42 treatment causes p21^WAF/CIP1 overexpression and histone hyperacetylation, and it inhibits DU-145 cell growth with an IC50 of 0.11 μM. [1] HDAC42's capacity to inhibit Akt signaling contributes to its effectiveness in inhibiting the growth of PC-3 and U87MG cells. The growth of PC-3 and LNCaP cells is inhibited by AR-42, with IC50 values of 0.48 μM and 0.3 μM, respectively. In PC-3 cells, AR-42 significantly reduces phospho-Akt, Bcl-xL, and survivin and has a significantly higher apoptogenic potency than SAHA. [3] In malignant mast cell lines, treatment with AR-42 causes growth inhibition, cell-cycle arrest, apoptosis, and activation of caspases-3/7. Treatment with AR-42 results in down-regulation of Kit through HSP70 up-regulation, disassociation between Kit and heat shock protein 90 (HSP90), and inhibition of Kit transcription. The expression of p-Akt, total Akt, phosphorylated STAT3/5 (pSTAT3/5), and total STAT3/5 is downregulated in response to AR-42 treatment. [6] AR-42 exhibits potent growth inhibition of Raji, 697, and JeKo-1 cells, with an IC50 of less than 0.61 μM. Additionally, AR-42 increases the susceptibility of CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), possibly by lowering c-FLIP. [7] By downregulating Akt/mTOR signaling and creating ER stress in hepatocellular carcinoma (HCC) cells, AR-42 treatment also promotes autophagy. [8]

ln Vivo

Treatment with 25 mg/kg and 50 mg/kg of AR-42 suppresses the growth of PC-3 tumor xenografts by 52% and 67%, respectively, while treatment with 50 mg/kg of SAHA suppresses growth by 31%. Mice treated with AR-42 exhibit significantly lower intratumoral levels of phospho-Akt and Bcl-xL compared to those treated with SAHA.[3] AR-42 administration not only completely prevents the progression of prostatic intraepithelial neoplasia (PIN) to poorly differentiated carcinoma in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, but it also shifts tumorigenesis to a more differentiated phenotype, suppressing absolute and relative urogenital tract weights by 86% and 85%, respectively.[5] In three different mouse models of B-cell cancer, AR-42 dramatically lowers leukocyte counts and extends survival without showing any signs of toxicity.[7]

Enzyme Assay

Using an HDAC assay kit, HDAC activity is measured. This assay is based on the observation that the biotinylated [³H]-acetyl histone H4 peptide bound to streptavidin agarose beads can be deacetylated through the action of DU-145 nuclear extract, which is high in HDAC activity. The HDAC activity is determined by measuring the amount of [³H]-acetate released into the supernatant. A positive control is employed, namely sodium butyrate (0.25-1 mM).

Cell Assay

For ninety-six hours, cells are exposed to varying concentrations of AR-42. After removing the medium, 150 μL of 0.5 mg/mL MTT in RPMI 1640 medium is added, and the cells are incubated for two hours at 37 °C in a CO2 incubator. After removing the supernatants from the wells, 200 μL of DMSO per well is used to solubilize the reduced MTT dye. At 570 nm, absorbance is measured on a plate reader.

Animal Protocol

Dissolved in methylcellulose/Tween 80; 50 mg/kg/day; Oral gavage

Intact male NCr athymic nude mice inoculated s.c. with PC-3 cells

References

[1]. J Med Chem . 2005 Aug 25;48(17):5530-5.

[2]. J Biol Chem . 2005 Nov 18;280(46):38879-87.

[3]. Clin Cancer Res . 2006 Sep 1;12(17):5199-206.

[4].Cancer Res . 2007 Jun 1;67(11):5318-27.

[5]. Cancer Res . 2008 May 15;68(10):3999-4009.

[6]. Blood . 2010 May 27;115(21):4217-25.

[7]. PLoS One . 2010 Jun 3;5(6):e10941.

[8]. Autophagy . 2010 Nov;6(8):1057-65.

Additional Infomation

(S)-HDAC-42 is an amidobenzoic acid.
AR-42 has been used in trials studying the treatment of Meningioma, Acoustic Neuroma, Testicular Lymphoma, Intraocular Lymphoma, and Vestibular Schwannoma, among others.
HDAC Inhibitor REC-2282 is an orally available phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, with potential antineoplastic activity. Upon oral administration, REC-2282 inhibits the catalytic activity of HDAC, which results in an accumulation of highly acetylated chromatin histones, the induction of chromatin remodeling and an altered pattern of gene expression. This leads to the inhibition of tumor oncogene transcription, and the selective transcription of tumor suppressor genes, which inhibits tumor cell division and induces tumor cell apoptosis. HDAC, an enzyme upregulated in many tumor types, deacetylates chromatin histone proteins.

Solubility Data

Solubility (In Vitro)

DMSO: 10~63 mg/mL (32.0~201.7 mM)

Water: <1 mg/mL

Ethanol: 50~63 mg/mL (160.1~201.7 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 5 mg/mL (16.01 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 2: ≥ 5 mg/mL (16.01 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

Solubility in Formulation 3: ≥ 5 mg/mL (16.01 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix well.

Solubility in Formulation 4: ≥ 1 mg/mL (3.20 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

Solubility in Formulation 5: ≥ 1 mg/mL (3.20 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

Solubility in Formulation 6: ≥ 1 mg/mL (3.20 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

Solubility in Formulation 7: 0.5% methylcellulose+0.2% Tween 80: 30mg/mL

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	3.2014 mL	16.0072 mL	32.0143 mL
	5 mM	0.6403 mL	3.2014 mL	6.4029 mL
	10 mM	0.3201 mL	1.6007 mL	3.2014 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

PeptideDB

AR-42 (HDAC-42, NSC-736012, OSU-42) 935881-37-1

CAS No.: 935881-37-1

Physicochemical Properties

Biological Activity

Solubility Data