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| Targets |
Nanatinostat targets histone deacetylases (HDACs), a family of enzymes that remove acetyl groups from histone proteins, leading to chromatin condensation and transcriptional repression. Nanatinostat is a class I selective HDAC inhibitor, potently inhibiting HDAC1, HDAC2, and HDAC3 with IC₅₀ values of 3, 4, and 7 nM, respectively. It is less potent against HDAC5 (IC₅₀ = 200 nM) and HDAC6 (IC₅₀ = 2,100 nM). By inhibiting HDAC, Nanatinostat results in an accumulation of highly acetylated histones, the induction of chromatin remodeling, and the re-expression of tumor suppressor genes. This leads to cell cycle arrest, differentiation, and apoptosis in cancer cells.
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| ln Vitro |
In vitro, Nanatinostat inhibits HDAC activity in cell-based assays. It inhibits tumor cell proliferation and induces apoptosis in various cancer cell lines. The compound's activity is typically assessed by measuring histone acetylation levels by Western blot using anti-acetyl-histone H3 or H4 antibodies. Treatment with Nanatinostat at concentrations ranging from 0.1 to 10 μM for 24-48 hours results in increased histone acetylation and reduced cell viability. The compound is more potent against class I HDACs (HDAC1, 2, 3) than against class II HDACs (HDAC5, 6). Nanatinostat has been studied for its effects on cancer cell proliferation and apoptosis.
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| ln Vivo |
In vivo, Nanatinostat is orally bioavailable and has been studied in animal models of cancer and neurodegenerative diseases. The compound's oral bioavailability allows for convenient dosing in preclinical studies. In tumor xenograft models, Nanatinostat administration results in tumor growth inhibition. The compound's effects on histone acetylation in vivo can be measured in tumor tissues by immunohistochemistry or Western blot. Nanatinostat has been investigated for the treatment of cancer and neurodegenerative diseases. The compound is a research tool for studying HDAC biology and therapeutic potential.
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| Enzyme Assay |
In vitro enzyme assays for Nanatinostat typically involve measuring the inhibition of recombinant HDAC enzymes using fluorogenic substrates. A typical protocol: recombinant human HDAC1, HDAC2, HDAC3, HDAC5, or HDAC6 is incubated with varying concentrations of Nanatinostat (0.01 nM to 10 μM) in assay buffer (50 mM Tris-HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl₂) for 30 minutes at 37°C. Fluorogenic substrate (e.g., Boc-Lys(Ac)-AMC) is added, and the reaction is incubated for 60-120 minutes. The reaction is stopped by the addition of developer solution, and fluorescence is measured at excitation 360 nm and emission 460 nm. IC₅₀ values are calculated from inhibition curves using nonlinear regression. Positive controls include trichostatin A or suberoylanilide hydroxamic acid. Each concentration is tested in triplicate, and experiments are repeated at least three times.
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| Cell Assay |
In vitro cell-based assays for Nanatinostat are performed using cancer cell lines such as HeLa, HCT116, or MCF-7. A typical protocol: cells are seeded in 96-well plates at 5,000-10,000 cells/well and allowed to adhere overnight. Cells are treated with Nanatinostat at concentrations ranging from 0.01 to 10 μM for 24-72 hours. Histone acetylation is measured by Western blot using anti-acetyl-histone H3 or H4 antibodies. Cell viability is assessed using MTT or CellTiter-Glo assays. Apoptosis is assessed by Annexin V/PI staining and flow cytometry. Cell cycle distribution is analyzed by propidium iodide staining. Each condition is tested in triplicate, and experiments are repeated at least three times.
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| Animal Protocol |
In vivo animal studies for Nanatinostat are conducted in mouse xenograft models of cancer. A typical protocol: immunocompromised mice are inoculated subcutaneously with cancer cells (e.g., HCT116 or MCF-7). When tumors reach 50-100 mm³, mice are randomized to receive Nanatinostat via oral gavage at doses of 10-100 mg/kg, daily or every other day, for 2-4 weeks. Tumor volumes are measured with calipers every 2-3 days, and body weight is monitored for toxicity. At study termination, tumors are harvested for histopathological examination and biomarker analysis (e.g., histone acetylation by IHC or Western blot). Efficacy is assessed by comparing tumor growth between treatment and vehicle control groups.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Nanatinostat have been characterized in preclinical studies. The compound is orally bioavailable. Following oral administration, Nanatinostat is absorbed and reaches therapeutic concentrations in the systemic circulation. Its half-life, volume of distribution, clearance, and protein binding have been evaluated in preclinical models. The compound is metabolized in the liver, likely via CYP450 enzymes, and its metabolites are eliminated via the renal and biliary routes. Specific pharmacokinetic parameters have been reported in preclinical studies. The compound is stable under recommended storage conditions (powder at -20°C; in solvent at -80°C).
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| Toxicity/Toxicokinetics |
Toxicological data for Nanatinostat have been evaluated in preclinical safety studies. The compound is generally well-tolerated at therapeutic doses. Common adverse effects may include gastrointestinal disturbances, fatigue, and hematological effects (thrombocytopenia, neutropenia), which are class effects of HDAC inhibitors. The compound has not been associated with significant organ toxicity in preclinical studies. Standard laboratory safety precautions should be followed when handling Nanatinostat: use of personal protective equipment (gloves, safety goggles, lab coat) and handling in a well-ventilated fume hood. The compound should be stored at -80°C for long-term stability. Researchers should consult the safety data sheet (SDS) before handling.
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| References | |
| Additional Infomation |
Nanatinostat is being investigated in the clinical trial NCT00697879 (Safety study of histone deacetylase inhibitor CHR-3996 in patients with advanced solid tumors). Nanatinostat is a highly bioavailable, second-generation hydroxamic acid histone deacetylase (HDAC) inhibitor with potential antitumor activity. Nanatinostat targets and inhibits HDAC, leading to the accumulation of highly acetylated histones, induction of chromatin remodeling, and selective transcription of tumor suppressor genes; these events ultimately result in the inhibition of tumor cell division and the induction of tumor cell apoptosis. Compared to some first-generation HDAC inhibitors, this drug may more significantly upregulate HSP70 and downregulate the anti-apoptotic protein Bcl-2. HDACs are upregulated in various tumor cell types and are a class of metalloenzymes responsible for the deacetylation of chromatin histones.
Additional information for Nanatinostat: The compound has a CAS number of 1256448-47-1. Synonyms include CHR-3996. It is an orally bioavailable, second-generation hydroxamic acid-based HDAC inhibitor. It is a potent, class I selective HDAC inhibitor with an IC₅₀ of 8 nM. IC₅₀s: HDAC1 = 3 nM, HDAC2 = 4 nM, HDAC3 = 7 nM, HDAC5 = 200 nM, HDAC6 = 2,100 nM. It inhibits tumor cell proliferation and induces apoptosis. It has been studied for cancer and neurodegenerative diseases. It is for research use only and is not approved for clinical applications. No FDA approvals exist. |
| Molecular Formula |
C20H19FN6O2
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|---|---|
| Molecular Weight |
394.402266740799
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| Exact Mass |
393.16
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| CAS # |
1256448-47-1
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| Related CAS # |
914937-68-1 (racemic);1256448-47-1;1256448-48-2 (TFA);2648504-17-8 (hydrate); 1256448-48-2 (TFA); 1235859-13-8 (deleted);
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| PubChem CID |
49857317
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| Appearance |
White to off-white solid powder
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| LogP |
1
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
29
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| Complexity |
592
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| Defined Atom Stereocenter Count |
2
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| SMILES |
FC1C=CC2=C(C=1)C=CC(CNC1C3CN(C4N=CC(C(NO)=O)=CN=4)CC31)=N2
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| InChi Key |
QRGHOAATPOLDPF-BYICEURKSA-N
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| InChi Code |
InChI=1S/C20H19FN6O2/c21-13-2-4-17-11(5-13)1-3-14(25-17)8-22-18-15-9-27(10-16(15)18)20-23-6-12(7-24-20)19(28)26-29/h1-7,15-16,18,22,29H,8-10H2,(H,26,28)/t15-,16+,18?
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| Chemical Name |
2-[(1S,5R)-6-[(6-fluoroquinolin-2-yl)methylamino]-3-azabicyclo[3.1.0]hexan-3-yl]-N-hydroxypyrimidine-5-carboxamide
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| Synonyms |
Tractinostat VRx-3996 CHR 3996 VRx3996CHR-3996 CHR3996
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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 (e.g. under nitrogen), 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 : ~50 mg/mL (~126.77 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.34 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 25.0 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: 2.5 mg/mL (6.34 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5355 mL | 12.6775 mL | 25.3550 mL | |
| 5 mM | 0.5071 mL | 2.5355 mL | 5.0710 mL | |
| 10 mM | 0.2535 mL | 1.2677 mL | 2.5355 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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