AR-42

Catalog No.S2244

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

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AR-42 Chemical Structure

AR-42 Chemical Structure
Molecular Weight: 312.36

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Product Information

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    Combination Therapy

Product Description

Biological Activity

Description AR-42 is an HDAC inhibitor with IC50 of 30 nM. Phase 1.
Targets HDAC [1]
IC50 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] HDAC42 is potent in suppressing the proliferation of U87MG and PC-3 cells, in part, because of its ability to down-regulate Akt signaling. [2] AR-42 inhibits the growth of PC-3 and LNCaP cells with IC50 of 0.48 μM and 0.3 μM, respectively. Compared to SAHA, AR-42 exhibits distinctly superior apoptogenic potency, and causes markedly greater decreases in phospho-Akt, Bcl-xL, and survivin in PC-3 cells. [3] AR-42 treatment induces growth inhibition, cell- cycle arrest, apoptosis, and activation of caspases-3/7 in malignant mast cell lines. AR-42 treatment induces down-regulation of Kit via inhibition of Kit transcription, disassociation between Kit and heat shock protein 90 (HSP90), and up-regulation of HSP70. AR-42 treatment down-regulates the expression of p-Akt, total Akt, phosphorylated STAT3/5 (pSTAT3/5), and total STAT3/5. [6] AR-42 potently inhibits the growth of JeKo-1, Raji, and 697 cells with IC50 of <0.61 μM. AR-42 also sensitizes CLL cells to TNF-Related Apoptosis Inducing Ligand (TRAIL), potentially through reduction of c-FLIP. [7] AR-42 treatment also induces autophagy through downregulation of Akt/mTOR signaling and inducing ER stress in hepatocellular carcinoma (HCC) cells. [8]
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 AR-42 treated mice. [3] In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, administration of AR-42 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] AR-42 significantly reduces leukocyte counts, and prolongs survival in three separate mouse models of B-cell malignancy without evidence of toxicity. [7]
Features Greater potency relative to SAHA.

Protocol(Only for Reference)

Kinase Assay:

[1]

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.

Cell Assay:

[1]

Cell lines DU-145
Concentrations Dissolved in DMSO, final concentrations ~2.5 μM
Incubation Time 96 hours
Method

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.

Animal Study:

[3]

Animal Models Intact male NCr athymic nude mice inoculated s.c. with PC-3 cells
Formulation Formulated in methylcellulose/Tween 80
Dosages ~50 mg/kg/day
Administration Orally

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Lu Q, et al. J Med Chem, 2005, 48(17), 5530-5535.

[2] Chen CS, et al. J Biol Chem, 2005, 280(46), 38879-38887.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02795819 Recruiting Renal Cell Carcinoma|Soft Tissue Sarcoma|Metastatic Disease Virginia Commonwealth University|Arno Therapeutics|Nation  ...more Virginia Commonwealth University|Arno Therapeutics|National Cancer Institute (NCI) July 2016 Phase 1
NCT02569320 Recruiting Recurrent Plasma Cell Myeloma Yvonne Efebera|Celgene|Ohio State University Comprehensiv  ...more Yvonne Efebera|Celgene|Ohio State University Comprehensive Cancer Center May 2016 Phase 1
NCT02282917 Recruiting Vestibular Schwannoma|Meningioma|Acoustic Neuroma|Neurofibromatosis Type 2 Massachusetts Eye and Ear Infirmary|Johns Hopkins Univers  ...more Massachusetts Eye and Ear Infirmary|Johns Hopkins University|Mayo Clinic|Stanford University|Ohio State University|Nationwide Childrens Hospital September 2015 Phase 0
NCT01798901 Active, not recruiting Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities|Adult Acute Myeloid Leukemia With Del(5q)|Adult Acute Myeloid Leukemia With Inv(16)(p13  ...more Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities|Adult Acute Myeloid Leukemia With Del(5q)|Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)|Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)|Adult Acute Myeloid Leukemia With t(16;16)(p13;q22)|Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)|Recurrent Adult Acute Myeloid Leukemia|Recurrent Childhood Acute Myeloid Leukemia|Secondary Acute Myeloid Leukemia|Untreated Adult Acute Myeloid Leukemia Alison Walker|Ohio State University Comprehensive Cancer  ...more Alison Walker|Ohio State University Comprehensive Cancer Center September 2013 Phase 1
NCT01129193 Active, not recruiting Adult Nasal Type Extranodal NK/T-cell Lymphoma|Anaplastic Large Cell Lymphoma|Angioimmunoblastic T-cell Lymphoma|Cutaneous B-cell Non-Hodgkin Lymph  ...more Adult Nasal Type Extranodal NK/T-cell Lymphoma|Anaplastic Large Cell Lymphoma|Angioimmunoblastic T-cell Lymphoma|Cutaneous B-cell Non-Hodgkin Lymphoma|Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue|Hepatosplenic T-cell Lymphoma|Intraocular Lymphoma|Nodal Marginal Zone B-cell Lymphoma|Peripheral T-cell Lymphoma|Post-transplant Lymphoproliferative Disorder|Prolymphocytic Leukemia|Recurrent Adult Burkitt Lymphoma|Recurrent Adult Diffuse Large Cell Lymphoma|Recurrent Adult Diffuse Mixed Cell Lymphoma|Recurrent Adult Diffuse Small Cleaved Cell Lymphoma|Recurrent Adult Grade III Lymphomatoid Granulomatosis|Recurrent Adult Hodgkin Lymphoma|Recurrent Adult Immunoblastic Large Cell Lymphoma|Recurrent Adult Lymphoblastic Lymphoma|Recurrent Adult T-cell Leukemia/Lymphoma|Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma|Recurrent Grade 1 Follicular Lymphoma|Recurrent Grade 2 Follicular Lymphoma|Recurrent Grade 3 Follicular Lymphoma|Recurrent Mantle Cell Lymphoma|Recurrent Marginal Zone Lymphoma|Recurrent Mycosis Fungoides/Sezary Syndrome|Recurrent Small Lymphocytic Lymphoma|Refractory Chronic Lymphocytic Leukemia|Refractory Multiple Myeloma|Stage III Adult Burkitt Lymphoma|Stage III Adult Diffuse Large Cell Lymphoma|Stage III Adult Diffuse Mixed Cell Lymphoma|Stage III Adult Diffuse Small Cleaved Cell Lymphoma|Stage III Adult Hodgkin Lymphoma|Stage III Adult Immunoblastic Large Cell Lymphoma|Stage III Adult Lymphoblastic Lymphoma|Stage III Adult T-cell Leukemia/Lymphoma|Stage III Chronic Lymphocytic Leukemia|Stage III Cutaneous T-cell Non-Hodgkin Lymphoma|Stage III Grade 1 Follicular Lymphoma|Stage III Grade 2 Follicular Lymphoma|Stage III Grade 3 Follicular Lymphoma|Stage III Mantle Cell Lymphoma|Stage III Marginal Zone Lymphoma|Stage III Multiple Myeloma|Stage III Mycosis Fungoides/Sezary Syndrome|Stage III Small Lymphocytic Lymphoma|Stage IV Adult Burkitt Lymphoma|Stage IV Adult Diffuse Large Cell Lymphoma|Stage IV Adult Diffuse Mixed Cell Lymphoma|Stage IV Adult Diffuse Small Cleaved Cell Lymphoma|Stage IV Adult Hodgkin Lymphoma|Stage IV Adult Immunoblastic Large Cell Lymphoma|Stage IV Adult Lymphoblastic Lymphoma|Stage IV Adult T-cell Leukemia/Lymphoma|Stage IV Chronic Lymphocytic Leukemia|Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma|Stage IV Grade 1 Follicular Lymphoma|Stage IV Grade 2 Follicular Lymphoma|Stage IV Grade 3 Follicular Lymphoma|Stage IV Mantle Cell Lymphoma|Stage IV Marginal Zone Lymphoma|Stage IV Mycosis Fungoides/Sezary Syndrome|Stage IV Small Lymphocytic Lymphoma|Testicular Lymphoma|Waldenstrom Macroglobulinemia Craig Hofmeister|National Cancer Institute (NCI)|Arno The  ...more Craig Hofmeister|National Cancer Institute (NCI)|Arno Therapeutics|Ohio State University Comprehensive Cancer Center May 2010 Phase 1

Chemical Information

Download AR-42 SDF
Molecular Weight (MW) 312.36
Formula

C18H20N2O3

CAS No. 935881-37-1
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms HDAC-42
Solubility (25°C) * In vitro DMSO 63 mg/mL (201.69 mM)
Ethanol 63 mg/mL (201.69 mM)
Water <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose+0.2% Tween 80 30 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.
Chemical Name (S)-N-hydroxy-4-(3-methyl-2-phenylbutanamido)benzamide

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
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