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

• ChemBase ID: 72471
• Molecular Formular: C18H20N2O3
• Molecular Mass: 312.363
• Monoisotopic Mass: 312.14739251
• SMILES: c1ccc(cc1)[C@@H](C(=O)Nc1ccc(cc1)C(=O)NO)C(C)C
• Canonical SMILES: ONC(=O)c1ccc(cc1)NC(=O)[C@H](c1ccccc1)C(C)C
• InChI: 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
• InChIKey: LAMIXXKAWNLXOC-INIZCTEOSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: N-hydroxy-4-[(2S)-3-methyl-2-phenylbutanamido]benzamide
• IUPAC Traditional name: N-hydroxy-4-[(2S)-3-methyl-2-phenylbutanamido]benzamide
• Synonyms: HDAC-42; (S)-HDAC 42; AR 42; OSU-HDAC 42; AR-42

Database IDs

• CAS Number: 935881-37-1
• PubChem SID: 162037396
• PubChem CID: 6918848

CALCULATED PROPERTIES

• Acid pKa: 9.799228
• H Acceptors: 3
• H Donor: 3
• LogD (pH = 5.5): 3.167307
• LogD (pH = 7.4): 3.1656077
• Log P: 3.1673286
• Molar Refractivity: 90.21 cm^3
• Polarizability: 33.772896 Å^3
• Polar Surface Area: 78.43 Å^2
• Rotatable Bonds: 5
• Lipinski's Rule of Five: true

PROPERTIES

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: HDAC

Product Information

• Salt Data: Free Base

DETAILS

Selleck Chemicals - S2244

Research Area

• Description: Multiple myeloma, Lymphoma, Chronic lymphocytic leukaemia

Biological Activity

• Description: AR-42 (HDAC-42, OSU-HDAC42) is a pan-HDAC inhibitor with IC50 30 nM.
• Targets: HDAC
• IC50: 30 nM ^[1]
• In Vitro: AR-42 treatment induces histone hyperacetylation and p21^WAF/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]
• Clinical Trials: A Phase I study of AR-42 in treating patients with advanced or relapsed multiple myeloma, chronic lymphocytic leukemia, or lymphoma is currently ongoing.
• Features: More potent than SAHA.

Combination Therapy

• Description: Pretreatment of DU-145 cells with 0.25 μM AR-42 augments the effect of bleomycin, doxorubicin, and VP-16, but not 5-FU, on clonogenic inhibition, by targeting Ku70 acetylation. ^[4]

Protocol

• Protocol: Kinase Assay ^[1]
• In vitro HDAC assay: HDAC activity is analyzed by using a 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.
• Protocol: Cell Assay ^[1]
• Cell Lines: DU-145
• Concentrations: Dissolved in DMSO, final concentrations ~2.5 μM
• Incubation Time: 96 hours
• Methods: 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.
• Protocol: Animal Study ^[3]
• Animal Models: Intact male NCr athymic nude mice inoculated s.c. with PC-3 cells
• Formulation: Formulated in methylcellulose/Tween 80
• Doses: ~50 mg/kg/day
• Administration: Orally

References

• References: [1] Lu Q, et al. J Med Chem, 2005, 48(17), 5530-5535.
• References: [2] Chen CS, et al. J Biol Chem, 2005, 280(46), 38879-38887.
• References: [3] Kulp SK, et al. Clin Cancer Res, 2006, 12(17), 5199-5206.
• References: [4] Chen CS, et al. Cancer Res, 2007, 67(11), 5318-5327.
• References: [5] Sargeant AM, et al. Cancer Res, 2008, 68(10), 3999-4009.
• References: [6] Lin TY, et al. Blood, 2010, 115(21), 4217-4225.
• References: [7] Lucas DM, et al. PLoS One, 2010, 5(6), e10941.

REFERENCES

• Lu Q, et al. J Med Chem, 2005, 48(17), 5530-5535.
• Chen CS, et al. J Biol Chem, 2005, 280(46), 38879-38887.
• Kulp SK, et al. Clin Cancer Res, 2006, 12(17), 5199-5206.
• Chen CS, et al. Cancer Res, 2007, 67(11), 5318-5327.
• Lin TY, et al. Blood, 2010, 115(21), 4217-4225.
• Lucas DM, et al. PLoS One, 2010, 5(6), e10941.
• Sargeant AM, et al. Cancer Res, 2008, 68(10), 3999-4009.