Quisinostat (JNJ-26481585) 2HCl
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.
Cited by 7 Publications
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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.
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|Description||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.|
|Features||An orally bioavailable, second-generation, hydroxamic acid-based HDAC inhibitor.|
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.  A recent study shows that JNJ-26481585 promotes myeloma cell death at low nanomolar concentrations by resulting in Mcl-1 depletion and Hsp72 induction. 
|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. |
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||
|In vitro||DMSO||79 mg/mL (169.02 mM)|
|In vivo||15% Captisol||30 mg/mL|
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Clinical Trial Information
|NCT Number||Recruitment||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT02948075||Active, not recruiting||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|
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