Quisinostat (JNJ-26481585) 2HCl

Catalog No.S1096

Molecular Weight(MW): 467.39

Quisinostat (JNJ-26481585) 2HCl is a novel second-generation HDAC inhibitor with highest potency for HDAC1 with IC50 of 0.11 nM in a cell-free assay, modest potent to HDACs 2, 4, 10, and 11; greater than 30-fold selectivity against HDACs 3, 5, 8, and 9 and lowest potency to HDACs 6 and 7. Phase 2.

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In vitro drug sensitivity of (C) quisinostat. Acute lymphoblastic leukemia cell lines (NALM-6, KOPN-30bi) and primary cultured cells established from patient 21 were cultured with the indicated concentrations of anticancer drugs, and viability was measured at 48 hours. Data are presented as percentages of dimethylsulfoxide (DMSO) control and depict the mean 6 standard deviation.

J Clin Oncol, 2016, 34(28):3451-9.. Quisinostat (JNJ-26481585) 2HCl purchased from Selleck.

(c) Acetylation site occupancies of histone H3 at positions K18 and K23 and (d) histone H4 at positions K5, K8, K12 and K16. Each bar graph represents the mean of two technical replicates with error bars showing the relative distance from the mean of the maximum and minimum values.

Nat Commun, 2015, 6:8648.. Quisinostat (JNJ-26481585) 2HCl purchased from Selleck.
F, Cells were treated with 15 nM JNJ-26481585 for 6 hours. Protein expression of acetylated histone H3 (Ac-H3), H3 and α-Tubulin was assessed by Western blotting.

Oncotarget, 2015, 6(35):37836-51.. Quisinostat (JNJ-26481585) 2HCl purchased from Selleck.

WT ESCs were treated with varying concentrations of the HDAC1 specific inhibitor JNJ-26481585 for 24 h. Lysates were collected for ChIP experiments, and a H3K27ac antibody was used for immunoprecipitation (IP). qPCR was performed using primers specific for Hoxa1 RARE2. ChIP with an IgG antibody (negative control) is included in each panel. Error bars represent standard error of independent experiments where n = 3 for biological repeats. *, p < 0.05.

J Biol Chem 2014 289(28), 19519-30. Quisinostat (JNJ-26481585) 2HCl purchased from Selleck.
Western blot analysis of Acetyl-H3 and H3. 0-10μM JNJ-26481585 was added.

Dr. Zhang of Tianjin Medical University. Quisinostat (JNJ-26481585) 2HCl purchased from Selleck.

Purity & Quality Control

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Biological Activity

Description

Features

An orally bioavailable, second-generation, hydroxamic acid-based HDAC inhibitor.

Targets

HDAC1 ^[1] (Cell-free assay)	HDAC2 ^[1] (Cell-free assay)	HDAC11 ^[1] (Cell-free assay)	HDAC10 ^[1] (Cell-free assay)	HDAC4 ^[1] (Cell-free assay)	View More
0.11 nM	0.33 nM	0.37 nM	0.46 nM	0.64 nM	View More

In vitro

JNJ-26481585 exhibits broad spectrum antiproliferative activity in solid and hematologic cancer cell lines, such as all lung, breast, colon, prostate, brain, and ovarian tumor cell lines, with IC50 ranging from 3.1-246 nM, which is more potent than vorinostat, R306465, panobinostat, CRA-24781, or mocetinostat in various human cancer cell lines tested. ^[1] A recent study shows that JNJ-26481585 promotes myeloma cell death at low nanomolar concentrations by resulting in Mcl-1 depletion and Hsp72 induction. ^[2]

In vivo

In an HDAC1-responsive A2780 ovarian tumor screening model, JNJ-26481585 dosing at its maximal tolerated dose (10 mg/kg i.p. and 40 mg/kg p.o.) for 3 days leads to an HDAC1-regulated fluorescence , which predicts tumor growth inhibition. Furthermore, JNJ-26481585 also shows more potent inhibitory effects on the growth of C170HM2 colorectal liver metastases than 5-fluorouracil/Leucovorin. ^[1]

Protocol

Kinase Assay:^[1]	+ Expand HDAC activity assays : In all cases, full-length HDAC proteins are expressed using baculovirus-infected Sf9 cells. In addition, HDAC3 is coexpressed as a complex with human NCOR2. For assessing activity of HDAC1-containing cellular complexes, immunoprecipitated HDAC1 complexes are incubated with an [³H]acetyl- labeled fragment of histone H4 peptide [biotin-(6-aminohexanoic)Gly-Ala-(acetyl[3H])Lys-Arg-His-Arg-Lys-Val-NH2] in a total volume of 50μL enzyme assay buffer (25mM HEPES (pH 7.4), 1 M sucrose, 0.1 mg/mL BSA and 0.01% (v/v) Triton X-100). Incubation is performed for 45 minutes at 37 °C (immunoprecipitates) or 30 min at room temperature. Before addition of substrate, HDAC inhibitors are added at increasing concentrations and preincubated for 10 minutes at room temperature. After incubation, the reaction is quenched with 35μL stop buffer (1 M HCl and 0.4 M acetic acid). Released [³H]acetic acid is extracted with 800μL ethyl acetate and quantified by scintillation counting. Equal amounts of HDAC1 are immunoprecipitated as indicated by Western blot analysis. HDAC1 activity results are presented as mean ± SD of three independent experiments on a single lysate.
Cell Research:Cell proliferation assays	+ Expand Cell lines: NCL-H2106, Colo699 and LNCAP cells Concentrations: 0-300 nM Incubation Time: 24 hours Method: All cell lines are obtained from American Type Culture Collection and cultured according to instructions. The effect of HDAC inhibitors on cell proliferation is measured using an MTT. Proliferation of non–small cell lung carcinoma (NSCLC) cell lines is assessed using an Alamar Blue–based assay. For proliferation of hematologic cell lines, cells are incubated for 72 hours and the cytotoxic activity is evaluated by MTS assay. Data are presented as mean IC50 or IC40 ± SD of at least three independent experiments. (Only for Reference)
Animal Research:^[1]	+ Expand Animal Models: HCT116 human colon carcinoma cells are injected s.c. into the inguinal region of athymic male NMRI nu/nu mice, C170HM2 cell suspensions are injected into the peritoneal cavity of male MFI nude mice. Formulation: JNJ-26481585 is formulated at 2 mg/mL in 20% hydroxypropyl-β-cyclodextrin (final pH 8.7). Dosages: ≤10 mg/kg Administration: Administered via both p.o. and i.p. (Only for Reference)

References

Solubility (25°C)

In vitro	DMSO	79 mg/mL (169.02 mM)
	Water	Insoluble
	Ethanol	Insoluble
In vivo	Add solvents to the product individually and in order(Data is from Selleck tests instead of citations): 2% DMSO+30% PEG 300+ddH2O For best results, use promptly after mixing.	5mg/mL

* 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 Information

Molecular Weight	467.39
Formula	C₂₁H₂₈Cl₂N₆O₂
CAS No.	875320-31-3
Storage	3 years -20°C powder
Storage	2 years -80°C in solvent
Synonyms	N/A

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Clinical Trial Information (data from https://clinicaltrials.gov, updated on 2018-11-16)

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT02948075	Completed	Ovarian Cancer	NewVac LLC\|Janssen Pharmaceutica N.V. Belgium	September 2015	Phase 2
NCT02728492	Completed	Non-small Cell Lung Cancer\|Epithelial Ovarian Cancer	NewVac LLC\|Janssen Pharmaceutica N.V. Belgium	August 2013	Phase 1
NCT01486277	Completed	Lymphoma T-Cell Cutaneous	Janssen Research & Development LLC	November 2011	Phase 2
NCT00676728	Terminated	Advanced or Refractory Leukemia\|Myelodysplastic Syndromes	Johnson & Johnson Pharmaceutical Research & Development L.L.C.	December 2008	Phase 1
NCT00677105	Completed	Lymphoma\|Neoplasms	Johnson & Johnson Pharmaceutical Research & Development L.L.C.\|Janssen Pharmaceutica N.V. Belgium	August 2007	Phase 1

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.

Handling Instructions

Tel: +1-832-582-8158 Ext:3

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Frequently Asked Questions

Question 1:
I was thinking of resuspending the powder in 10% hydroxy-propyl-β-cyclodextrin, 25mg/ml mannitol, in sterile water (final pH 8.7). Is this a good vehicle to use? What is the solubility of this chemical in such a vehicle?
Answer:
This vehicle can be used for in vivo studies. The following papers also used this vehicle: 1. http://www.nature.com/leu/journal/v23/n10/full/leu2009121a.html; 2. http://cancerres.aacrjournals.org/content/69/13/5307.long (The solvent contains 10% hydroxypropyl-β-cyclodextrin, 0.8% HCl (0.1 N), 0.9 % NaOH (0.1 N), 3.4% mannitol and pyrogen-free water). The solubility is 2mg/ml.

HDAC Signaling Pathway Map

HDAC Inhibitors with Unique Features

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FDA-approved HDAC Inhibitor

Vorinostat (SAHA, MK0683) : Approved by FDA against cutaneous T cell lymphoma.
Newest HDAC Inhibitor

RG2833 (RGFP109) ^New : Brain-penetrant HDAC inhibitor with IC50 of 60 nM and 50 nM for HDAC1 and HDAC3, respectively.
Classic HDAC Inhibitor

Panobinostat (LBH589) : Novel broad-spectrum HDAC inhibitor with IC50 of 5 nM.

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CAY10603 is a potent and selective HDAC6 inhibitor with IC50 of 2 pM, >200-fold selectivity over other HDACs.
Domatinostat (4SC-202) ^New

4SC-202 is a selective class I HDAC inhibitor with IC50 of 1.20 μM, 1.12 μM, and 0.57 μM for HDAC1, HDAC2, and HDAC3, respectively. Also displays inhibitory activity against Lysine specific demethylase 1 (LSD1). Phase 1.
Panobinostat (LBH589)

Panobinostat (LBH589) is a novel broad-spectrum HDAC inhibitor with IC50 of 5 nM in a cell-free assay. Phase 3.
Vorinostat (SAHA, MK0683)

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is an HDAC inhibitor with IC50 of ~10 nM in a cell-free assay.
Entinostat (MS-275)

Entinostat (MS-275) strongly inhibits HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM in cell-free assays, compared with HDACs 4, 6, 8, and 10. Phase 3.
Trichostatin A (TSA)

Trichostatin A (TSA) is an HDAC inhibitor with IC50 of ~1.8 nM in cell-free assays.
Romidepsin (FK228, Depsipeptide)

Romidepsin (FK228, depsipeptide) is a potent HDAC1 and HDAC2 inhibitor with IC50 of 36 nM and 47 nM in cell-free assays, respectively.

Features:More effective than other classical HDAC inhibitors such as TSA, TPX, and butyrate.
RGFP966

RGFP966 is an HDAC3 inhibitor with IC50 of 0.08 μM in cell-free assay, exhibits > 200-fold selectivity over other HDAC.
Tubastatin A

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Quisinostat (JNJ-26481585) 2HCl