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| Targets |
Pan-histone deacetylase (HDAC) inhibitor. IC50 values against recombinant HDAC enzymes: HDAC1 0.11 ± 0.03 nM, HDAC2 0.33 ± 0.06 nM, HDAC3 4.86 ± 0.69 nM, HDAC4 0.64 ± 0.18 nM, HDAC5 3.69 ± 0.63 nM, HDAC6 76.8 ± 6.35 nM, HDAC7 119 ± 3.61 nM, HDAC8 4.26 ± 2.97 nM, HDAC9 32.1 ± 4.77 nM, HDAC10 0.46 ± 0.07 nM, HDAC11 0.37 ± 0.08 nM [1].
Inhibits HDAC1 complexes immunoprecipitated from A2780 ovarian carcinoma cells with IC50 0.16 ± 0.02 nM [1]. HDAC1 0.11 nM (IC50); HDAC2 0.33 nM (IC50); HDAC11 0.37 nM (IC50); HDAC10 0.46 nM (IC50); HDAC5 3.69 nM (IC50); HDAC8 4.26 nM (IC50); HDAC3 4.86 nM (IC50); HDAC9 32.1 nM (IC50); HDAC6 76.8 nM (IC50); HDAC7 119 nM (IC50) |
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| ln Vitro |
In vitro, JNJ-26481585 suppresses HDAC isozymes[1]. In tumor cells, JNJ-26481585 (30–1000 nM; 24 hours) is a strong pan-HDAC inhibitor[1]. JNJ-26481585 causes apoptosis and exhibits broad spectrum antiproliferative action against hematologic and solid cancer cell lines[1].
In A2780 ovarian carcinoma cells, JNJ-26481585 induced H3 and H4 acetylation at concentrations as low as 30-100 nM, induced acetylation and trimethylation at Lys16 and Lys20 of histone H4, and upregulated p21waf1,cip1 and E-cadherin. It also induced tubulin acetylation and Hsp70 induction with loss of Hsp90 client c-Raf at 30-100 nM [1]. JNJ-26481585 inhibited proliferation of solid tumor cell lines (lung, breast, colon, prostate, brain, ovarian) with IC50 values ranging from 3.1 to 246 nM, and hematologic tumor cell lines (ALL, AML, CLL, CML, lymphoma, myeloma) with IC40 values of 4.5-166 nM. It induced apoptosis in a concentration-dependent manner at 3-300 nM [1]. In multiple myeloma cell lines, JNJ-26481585 induced cell death with EC50 values of 1-20 nM and EC90 values of 1.4-37 nM. Molecular effects included histone H3/H4 acetylation, tubulin acetylation, PARP cleavage, p21WAF/CIP upregulation, Hsp72 induction, attenuation of phospho-STAT3 and phospho-ERK1/2 signals, Mcl-1 downregulation, and pro-apoptotic shift in Bcl-2 family members (Bim upregulation, Bid cleavage). The pan-caspase inhibitor z-VAD-fmk delayed annexin V positivity in some cell lines [2]. In primary multiple myeloma cells (n=42) cocultured with bone marrow stromal cells, JNJ-26481585 induced cell death with EC50 values mostly in the 1-20 nM range. Molecular effects included histone H4 acetylation (heterogeneous), consistent Hsp72 upregulation, Mcl-1 downregulation (when expressed), phospho-STAT3 attenuation, and PARP cleavage [2]. |
| ln Vivo |
p21waf1,cip1 ZsGreen tumors in vivo with JNJ-26481585 (40 mg/kg; po; once daily, for 3 days) as a strong HDAC1 inhibitor[1]. In vivo, JNJ-26481585 consistently causes H3 acetylation in tumor tissue[1]. Large pre-established HCT116 colon xenografts are vigorously inhibited in their growth by JNJ-26481585 (10 mg/kg; once daily; ip; for 14 days)[1].
In mice bearing A2780-p21waf1,cip1 ZsGreen ovarian tumor xenografts, oral administration of JNJ-26481585 (40 mg/kg once daily for 3 days) induced bright and intense fluorescence in tumor tissue, indicating HDAC1 inhibition. R306465 (40 mg/kg) and vorinostat (200 mg/kg) showed only weak induction [1]. In HCT116 colon carcinoma xenografts (320 ± 10 mm³ at start), JNJ-26481585 (10 mg/kg i.p. once daily for 14 days) inhibited tumor volume by 76% (treated vs control = 24), superior to 5-FU (41% inhibition) and vorinostat (26% inhibition). Dose-dependent efficacy was observed at 2.5, 5, 10, and 20 mg/kg [1]. In C170HM2 colorectal liver metastasis model, JNJ-26481585 (5 mg/kg i.p. once daily from day 7 to day 40) potently inhibited liver tumor growth, whereas 5-FU/Leucovorin showed modest activity [1]. In A2780 ovarian xenografts, once daily dosing of JNJ-26481585 induced continuous histone H3 acetylation in tumor tissue. The plasma concentration resulting in 50% inhibition of histone deacetylation rate (IC50) was 5.9 ng/mL (14 nM) in A2780 tumors and 7.9 ng/mL (18 nM) in HCT116 tumors [1]. |
| Enzyme Assay |
Recombinant HDAC activity assays were performed using full-length HDAC proteins expressed in baculovirus-infected Sf9 cells (HDAC3 co-expressed with human NCOR2). Enzymes were incubated with test compounds at concentrations ranging from 0.1 nM to 10 μM. IC50 values were calculated [1].
For HDAC1 complex activity, HDAC1 was immunoprecipitated from A2780 ovarian carcinoma cells and incubated with a [³H]acetyl-labeled fragment of histone H4 peptide. Equal amounts of HDAC1 were confirmed by Western blot. Results are presented as mean ± SD of three independent experiments [1]. For pharmacodynamic modeling, tumor tissue was homogenized and H3 acetylation was determined by ELISA or MSD. An anti-histone PAN antibody was spotted onto a 96-well plate. After blocking, xenograft sample (2.5 μg/25 μL) or calibrator sample was added, and the array was incubated with anti-histone H3 antibody. Results were read using a Sector Imager 6000 [1]. |
| Cell Assay |
Western Blot Analysis[1]
Cell Types: Human A2780 ovarian carcinoma cells Tested Concentrations: 30 nM, 100 nM, 300 nM, 1000 nM Incubation Duration: 24 hrs (hours) Experimental Results: Induced H3 and H4 acetylation at concentrations as low as 30 to 100 nM. For cell proliferation, cells were incubated with JNJ-26481585 for 72-96 h. Viable cells were assessed using MTT colorimetric assay, Alamar Blue assay, or MTS assay. IC50/IC40 values were calculated from at least three independent experiments [1]. For apoptosis, human tumor cells were incubated with indicated concentrations of JNJ-26481585 for 24, 48, and 96 h. Cells were stained with Annexin V and 7-AAD or propidium iodide, and analyzed by flow cytometry. Results are expressed as percentage of apoptotic/necrotic cells [1][2]. For Western blot, cells were lysed in buffer containing 1% SDS. Proteins were separated by SDS-PAGE, transferred to membranes, and probed with antibodies against acetylated histones, acetylated tubulin, p21, Hsp72, Mcl-1, Bcl-2 family members, phospho-STAT3, phospho-ERK1/2, PARP, and loading controls (actin, lamin B1) [1][2]. For primary multiple myeloma cells, CD138-positive cells were isolated from bone marrow aspirates using magnetic beads. Cells were cultured in coculture with primary bone marrow stromal cells or in medium supplemented with IL-6. Cell death was assessed by annexin V/PI staining after 3-day drug exposure [2]. For drug combination studies, cells were treated with JNJ-26481585 combined with melphalan, doxorubicin, or bortezomib at fixed ratios based on EC50 values. Combination Index (CI) values were calculated using CalcuSyn software according to the median effect principle of Chou and Talalay. CI=1 indicates additivity, <1 synergy, >1 antagonism [2]. |
| Animal Protocol |
Animal/Disease Models: NMRI nude mice, with HCT116 colon carcinoma cells xenografts[1]
Doses: 10 mg/kg Route of Administration: intraperitoneal (ip)injection, one time/day, for 14 days Experimental Results: Strongly inhibited the growth of large pre-established HCT116 colon xenografts. |
| ADME/Pharmacokinetics |
In nude mice, JNJ-26481585 has a short plasma half-life due to extensive rodent-specific first-pass metabolism. The time course of drug concentration in plasma over the study duration was described by a two-compartment disposition model. The maximum exposure in plasma was observed at 30 minutes post-dose, while the maximum AcH3 response in tumor was observed 2-5 hours post-dose. The plasma concentration resulting in 50% inhibition of histone deacetylation rate was 5.9 ng/mL (14 nM) in A2780 tumors and 7.9 ng/mL (18 nM) in HCT116 tumors. Tumor concentrations on days 14 and 21 showed continuous exposure of HDAC1 to JNJ-26481585 in tumor tissue [1].
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| Toxicity/Toxicokinetics |
The maximal tolerated dose of JNJ-26481585 in mice (after a 20-day dosing period) was determined as the dose that resulted in <15% weight loss and no lethality [1].
In cell-based assays, JNJ-26481585 showed potent anti-proliferative activity across a broad panel of cancer cell lines with EC50 values in the low nanomolar range [1][2]. |
| References |
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| Additional Infomation |
JNJ-26481585 is a pyrimidyl-hydroxamic acid analogue identified as a "second-generation" oral HDAC inhibitor with prolonged pharmacodynamic response in vivo. It was selected from 140 analogues using an in vivo screening model where HDAC1-regulated p21waf1,cip1 promoter controls fluorescent ZsGreen protein expression [1].
The compound shows broad-spectrum preclinical antitumoral activity in both solid and hematologic malignancies. It is currently in clinical studies (Phase I trials) for solid malignancies and leukemia/lymphoma [1][2]. In primary multiple myeloma cells, Hsp72 upregulation, Mcl-1 downregulation, and phospho-STAT3 attenuation were identified as the most consistent molecular readouts of JNJ-26481585 treatment [2]. |
| Molecular Formula |
C21H28CL2N6O2
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|---|---|
| Molecular Weight |
467.39
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| Exact Mass |
466.165
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| Elemental Analysis |
C, 53.97; H, 6.04; Cl, 15.17; N, 17.98; O, 6.85
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| CAS # |
875320-31-3
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| Related CAS # |
Quisinostat;875320-29-9; 1083078-98-1 (HCl); 875320-31-3 (2HCl)
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| PubChem CID |
122129987
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| Appearance |
White to yellow solid powder
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
533
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CN1C=C(C2=CC=CC=C21)CNCC3CCN(CC3)C4=NC=C(C=N4)C(=O)NO.Cl.Cl
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| InChi Key |
NRUIZESXVMJDKR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H26N6O2.2ClH/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);2*1H
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| Chemical Name |
N-hydroxy-2-[4-[[(1-methylindol-3-yl)methylamino]methyl]piperidin-1-yl]pyrimidine-5-carboxamide;dihydrochloride
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| Synonyms |
Quisinostat dihydrochloride; JNJ26481585 dihydrochloride; JNJ-26481585 diHCl; Quisinostat (JNJ-26481585) 2HCl; JNJ-26481585 dihydrochloride; Quisinostat 2HCl; Quisinostat (dihydrochloride);
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : 31.25 mg/mL (66.86 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.45 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.45 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1395 mL | 10.6977 mL | 21.3954 mL | |
| 5 mM | 0.4279 mL | 2.1395 mL | 4.2791 mL | |
| 10 mM | 0.2140 mL | 1.0698 mL | 2.1395 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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