JNJ-26481585

Potent HDAC inhibitor CAS# 875320-29-9

JNJ-26481585

Catalog No. BCC2147----Order now to get a substantial discount!

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Chemical structure

JNJ-26481585

3D structure

Chemical Properties of JNJ-26481585

Cas No. 875320-29-9 SDF Download SDF
PubChem ID 11538455 Appearance Powder
Formula C21H26N6O2 M.Wt 394.48
Type of Compound N/A Storage Desiccate at -20°C
Synonyms JNJ-26481585
Solubility DMSO : 50 mg/mL (126.75 mM; Need ultrasonic)
Chemical Name N-hydroxy-2-[4-[[(1-methylindol-3-yl)methylamino]methyl]piperidin-1-yl]pyrimidine-5-carboxamide
SMILES CN1C=C(C2=CC=CC=C21)CNCC3CCN(CC3)C4=NC=C(C=N4)C(=O)NO
Standard InChIKey PAWIYAYFNXQGAP-UHFFFAOYSA-N
Standard InChI InChI=1S/C21H26N6O2/c1-26-14-17(18-4-2-3-5-19(18)26)11-22-10-15-6-8-27(9-7-15)21-23-12-16(13-24-21)20(28)25-29/h2-5,12-15,22,29H,6-11H2,1H3,(H,25,28)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of JNJ-26481585

DescriptionQuisinostat (JNJ-26481585) is a novel second-generation inhibitor of HDAC with highest potency for HDAC1 with IC50 of 0.11 nM.
TargetsHDAC1HDAC2HDAC4HDAC10HDAC11  
IC500.11 nM0.33 nM0.64 nM0.46 nM0.37 nM  

Protocol

Kinase experiment [1]:

Inhibitory activities

Recombinant HDAC activity assays were done by Reaction Biology Corporation. In all cases, full-length HDAC proteins were expressed using baculovirus-infected Sf9 cells. In addition, HDAC3 was coexpressed as a complex with human NCOR2. For assessing activity of HDAC1-containing cellular complexes, immunoprecipitated HDAC1 complexes were incubated with an [3H]acetyllabeled fragment of histone H4 peptide [biotin-(6-aminohexanoic)Gly-Ala-(acetyl[3H])Lys-Arg-His-Arg-Lys-Val-NH2]. Equal amounts of HDAC1 were immunoprecipitated as indicated by Western blot analysis. HDAC1 activity results are presented as mean ± SD of three independent experiments on a single lysate.

Cell experiment [1]:

Cell lines

Non-small cell lung carcinoma (NSCLC) cell lines; hematologic cell lines; human tumor cells; human A2780 ovarian carcinoma cells.

Preparation method

Soluble in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

cell proliferation: 72 h, apoptosis assays: 24, 48, and 96 h.

Applications

In all lung, breast, colon, prostate, brain, and ovarian tumor cell lines tested, JNJ-26481585 inhibits cell proliferation with IC50 values of 3.1-246 nM. In A2780 ovarian tumor cells, JNJ-26481585 (3-300 nM) significantly and dose-dependently increases the amount of cells positive for Annexin V, which indicates apoptosis.

Animal experiment [1]:

Animal models

Male athymic nu/nu CD-1 mice injected s.c. with human A2780-p21waf1,cip1 ZsGreen ovarian tumors cells

Dosage form

10 mg/kg i.p. and 40 mg/kg p.o.; once daily for 3 d.

Preparation method

Formulated at 2 mg/mL in 20% hydroxypropyl-β-cyclodextrin (final pH 8.7).

Application

In the HDAC1-responsive A2780 ovarian tumor screening model, JNJ-26481585 induces a bright and intense fluorescence, which is not uniformly distributed throughout the tissue and fully predicts tumor growth inhibition. Also, JNJ-26481585 induces potent H3 acetylation in the tumor tissue. In HCT116 colon xenografts, JNJ-26481585 (once daily, 10 mg/kg i.p.) for 14 days inhibits tumor volume by 76% and induces H3 acetylation.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Arts J, King P, Marin A, et al. JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin Cancer Res, 2009, 15(22): 6841-6851.

JNJ-26481585 Dilution Calculator

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Preparing Stock Solutions of JNJ-26481585

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.535 mL 12.6749 mL 25.3498 mL 50.6997 mL 63.3746 mL
5 mM 0.507 mL 2.535 mL 5.07 mL 10.1399 mL 12.6749 mL
10 mM 0.2535 mL 1.2675 mL 2.535 mL 5.07 mL 6.3375 mL
50 mM 0.0507 mL 0.2535 mL 0.507 mL 1.014 mL 1.2675 mL
100 mM 0.0253 mL 0.1267 mL 0.2535 mL 0.507 mL 0.6337 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of JNJ-26481585

1. Initial testing (stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program. Pediatr Blood Cancer. 2014 Feb;61(2):245-52. doi: 10.1002/pbc.24724. Epub 2013 Sep 4.
Abstract
JNJ-26481585, a selective inhibitor of Class I and II HDACs, exhibited prolonged pharmacodynamic effects in vivo and displayed higher antitumoral efficacy as a signle agent.
2. Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585. Eur J Hum Genet. 2013 Jun;21(6):643-52. doi: 10.1038/ejhg.2012.222. Epub 2012 Oct 17.
Abstract
JNJ-26481585, a pan-HDACi, up-regulated SMN levels in SMA fibroblast cell lines but failed to prolong survival in SMA mice despite mild improvements in motor abilities and weight progression.
4. Preclinical anti-myeloma activity of the novel HDAC-inhibitor JNJ-26481585. Br J Haematol. 2010 May;149(4):529-36. doi: 10.1111/j.1365-2141.2010.08126.x. Epub 2010 Mar 13.
Abstract
The treatment of JNJ-26481585 resulted in histone acetylation, a shift in Bcl2-family members towards proapoptotic bias, attenuation of growth and survival pathway activity and Hsp72 induction in both human MM cells and primary MM samples, where Mcl-1 depletion and Hsp72 induction were two reliable features observed in primary MM samples. JNJ-26481585 alone or in combination with anti-myeloma therapeutic agents induced myeloma cell death.
5. Preclinical antileukemia activity of JNJ-26481585, a potent second-generation histone deacetylase inhibitor. Leuk Res. 2010 Feb;34(2):221-8. doi: 10.1016/j.leukres.2009.07.024. Epub 2009 Aug 13.
Abstract
JNJ-26481585 alone or in combination with decitabine exhibits anti-leukemia activity in leukemia cell lines and primary human leukemia cells.

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Background on JNJ-26481585

JNJ-26481585 is a novel histone deacetylase (HDAC) inhibitor that exerts a strong potency towards class I HDAC (including HDAC1, HDAC2 and HDAC3), with values of inhibition constant IC50 of 0.11, 0.33 and 4.8 nmol/L respectively, leading to strong anti-proliferative activities (IC50 ranging from 3.1 to 246 nmol/L) against a broad range of cancer cell lines including lung, breast, colon, prostate, brain and overian cancer cell lines. Recent study results have shown that JNJ-26481585 strongly induce the HDAC1-suppressed p21waf1,cip1 promoter in vivo, histone H3 acetylation in tumor tissue and apoptosis in human colon cancer cell lines (both APC wild-type and mutant) in vitro.

Reference

Arts J, King P, Mariën A, Floren W, Beliën A, Janssen L, Pilatte I, Roux B, Decrane L, Gilissen R, Hickson I, Vreys V, Cox E, Bol K, Talloen W, Goris I, Andries L, Du Jardin M, Janicot M, Page M, van Emelen K, Angibaud P. JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity. Clin Cancer Res. 2009;15(22):6841-6851

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References on JNJ-26481585

Initial testing (stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ-26481585), by the Pediatric Preclinical Testing Program.[Pubmed:24038993]

Pediatr Blood Cancer. 2014 Feb;61(2):245-52.

BACKGROUND: Quisinostat (JNJ-26481585) is a second-generation pyrimidyl-hydroxamic acid histone deacetylase (HDAC) inhibitor with high cellular potency towards Class I and II HDACs. Quisinostat was selected for clinical development as it showed prolonged pharmacodynamic effects in vivo and demonstrated improved single agent antitumoral efficacy compared to other analogs. PROCEDURES: Quisinostat was tested against the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10 muM and was tested against the PPTP in vivo panels at a dose of 5 mg/kg (solid tumors) or 2.5 mg/kg (ALL models) administered intraperitoneally daily x 21. RESULTS: In vitro quisinostat demonstrated potent cytotoxic activity, with T/C% values approaching 0% for all of the cell lines at the highest concentration tested. The median relative IC50 value for the PPTP cell lines was 2.2 nM (range <1-19 nM). quisinostat induced significant differences in EFS distribution compared to control in 21 of 33 (64%) of the evaluable solid tumor xenografts and in 4 of 8 (50%) of the evaluable ALL xenografts. An objective response was observed in 1 of 33 solid tumor xenografts while for the ALL panel, two xenografts achieved complete response (CR) or maintained CR, and a third ALL xenograft achieved stable disease. CONCLUSIONS: Quisinostat demonstrated broad activity in vitro, and retarded growth in the majority of solid tumor xenografts studied. The most consistent in vivo activity signals observed were for the glioblastoma xenografts and T-cell ALL xenografts.

Effect of histone deacetylase inhibitor JNJ-26481585 in pain.[Pubmed:25085711]

J Mol Neurosci. 2015 Mar;55(3):570-8.

Recent studies have shown that histone deacetylase (HDAC) inhibitors can alleviate inflammatory and neuropathic pain. We investigated the effects of JNJ-26481585, a pan-HDAC inhibitor on basal mechanical sensitivity. Unlike previous reports for HDAC inhibitors, JNJ-26481585 induced mechanical hypersensitivity in mice. This effect was reversible with gabapentin. Voltage-dependent calcium channel subunit alpha-2/delta-1, one of the putative targets for gabapentin, was upregulated in the spinal cord from JNJ-26481585-treated mice. Transcriptional profiling of spinal cord from JNJ-26481585-treated mice showed significant alterations in pathways involved in axon guidance, suggesting overlap in mechanisms underlying neurotoxicity caused by other known chemotherapeutic agents. To investigate the mechanisms underlying the development of pain, RAW 264.7 mouse macrophage cells were treated with JNJ-26481585. There was a dose- and time-dependent activation of nuclear factor-kappaB and interleukin-1beta increase. Thus, alterations in the axon guidance pathway, increase in voltage-dependent calcium channel alpha(2)delta-1 subunit, and the induction of proinflammatory mediators by JNJ-26481585 could all contribute to increased mechanical sensitivity. Our data indicate that the effect of HDAC inhibitors may be unique to the compound studied and highlights the potential to develop chemotherapy-induced peripheral neuropathy with the use of a pan-HDAC inhibitor for cancer treatment, and this pain may be alleviated by gabapentin.

Critical role of mitochondria-mediated apoptosis for JNJ-26481585-induced antitumor activity in rhabdomyosarcoma.[Pubmed:26616861]

Oncogene. 2016 Jul 14;35(28):3729-41.

JNJ-26481585 is a second-generation histone deacetylase inhibitor with broad-range efficacy and improved pharmacodynamic properties. In the present study, we investigated the therapeutic potential of JNJ-26481585 and its molecular mechanisms of action in rhabdomyosarcoma (RMS). Here, we report that JNJ- 26481585's anticancer activity critically depends on an intact mitochondrial pathway of apoptosis. JNJ-26481585 induces apoptosis and also inhibits long-term clonogenic survival of several RMS cell lines at nanomolar concentrations that cause histone acetylation. Importantly, JNJ-26481585 significantly suppresses tumor growth in vivo in two preclinical RMS models, that is, the chorioallantoic membrane model and a xenograft mouse model. Mechanistically, we identify activation of the mitochondrial pathway of apoptosis as a key event that is critically required for JNJ-26481585-mediated cell death. JNJ-26481585 upregulates expression levels of several BH3-only proteins including Bim, Puma and Noxa, which all contribute to JNJ-26481585-mediated apoptosis, as knockdown of Bim, Puma or Noxa significantly inhibits cell death. This shift toward proapoptotic Bcl-2 proteins promotes activation of Bax and Bak as a critical event, as genetic silencing of Bax or Bak protects against JNJ-26481585-induced apoptosis. Intriguingly, rescue experiments reveal that JNJ-26481585 triggers Bax/Bak activation independently of caspase activation and activates caspase-9 as the initiator caspase in the cascade, as Bcl-2 overexpression, but not the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) blocks JNJ-26481585-induced Bax/Bak activation and caspase-9 cleavage. In conclusion, JNJ-26481585 exerts potent antitumor activity against RMS in vitro and in vivo by engaging mitochondrial apoptosis before caspase activation and represents a promising therapeutic for further investigation in RMS.

JNJ-26481585 primes rhabdomyosarcoma cells for chemotherapeutics by engaging the mitochondrial pathway of apoptosis.[Pubmed:26473375]

Oncotarget. 2015 Nov 10;6(35):37836-51.

Rhabdomyosarcoma (RMS) is a common soft-tissue sarcoma in childhood with a poor prognosis, highlighting the need for new treatment strategies. Here we identify a synergistic interaction of the second-generation histone deacetylase inhibitor (HDACI) JNJ-26481585 and common chemotherapeutic drugs (i.e. Doxorubicin, Etoposide, Vincristine, Cyclophosphamide and Actinomycin D) to trigger apoptosis in RMS cells. Importantly, JNJ-26481585/Doxorubicin cotreatment also significantly suppresses long-term clonogenic survival of RMS cells and tumor growth in vivo in a preclinical RMS model. Mechanistically, JNJ-26481585/Doxorubicin cotreatment causes upregulation of the BH3-only proteins Bim and Noxa as well as downregulation of the antiapoptotic proteins Mcl-1 and Bcl-xL. These changes in the ratio of pro- and antiapoptotic Bcl-2 proteins contribute to JNJ-26481585/Doxorubicin-mediated apoptosis, since knockdown of Bim or Noxa significantly inhibits cell death. Also, JNJ-26481585 and Doxorubicin cooperate to stimulate activation of Bax and Bak, which is required for JNJ-26481585/Doxorubicin-induced apoptosis, since silencing of Bax or Bak protects against apoptosis. Consistently, overexpression of Bcl-2 significantly reduces JNJ-26481585/Doxorubicin-mediated apoptosis. JNJ-26481585/Doxorubicin cotreatment leads to caspase activation and caspase-dependent apoptosis, since the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) rescues cells from apoptosis. In conclusion, the second-generation HDACI JNJ-26481585 cooperates with chemotherapeutics to engage mitochondrial apoptosis in RMS cells, demonstrating that JNJ-26481585 represents a promising strategy for chemosensitization of RMS.

Description

Quisinostat (JNJ-26481585) is an orally available, potent HDAC inhibitor with IC50s of 0.11 nM, 0.33 nM, 0.64 nM, 0.46 nM, and 0.37 nM for HDAC1, HDAC2, HDAC4, HDAC10, HDAC11, respectively.

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