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Purity: ≥98%
Remetinostat (formerly known as SHP-141) is an inhibitor of histone deacetylase (HDAC) developed by Medivir as a topical application for use in early stage CTCL (Cutaneous T-cell lymphoma). HDAC inhibitors are not advised for use in early-stage patients because of their severe side effects, but they are approved for the treatment of CTCL in late-stage patients. Because of its special design, remetinostat can be applied topically and acts only on the skin. It is broken down as soon as it enters the bloodstream, so it doesn't have the negative effects of other HDAC inhibitors. Remetinostat showed promise in treating skin lesions, reducing itching, and improving patient compliance in patients with early-stage colorectal cancer (CTCL) in the phase II trial.
| Targets |
HDAC
Histone deacetylase (HDAC), with IC50 values of 0.15 μM (HDAC1), 0.23 μM (HDAC2), 0.31 μM (HDAC3), 0.87 μM (HDAC6), and 1.25 μM (HDAC8) [1] |
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| ln Vitro |
In vitro activity: Kinase Assay: Cell Assay: Treatment of human acute myeloid leukemia (AML) cells (HL-60) with Remetinostat resulted in dose-dependent inhibition of cell proliferation, with an IC50 value of 0.72 μM after 72 hours of incubation [1] - Remetinostat induced acetylation of histone H3 (Lys9) and α-tubulin in HL-60 cells in a concentration-dependent manner, as detected by western blot analysis; significant acetylation was observed at concentrations ≥0.5 μM [1] - In human breast cancer cells (MCF-7), Remetinostat inhibited cell growth with an IC50 of 1.05 μM after 72 hours, accompanied by increased expression of p21WAF1/CIP1 and decreased expression of cyclin D1, as determined by PCR and western blot [1] |
| ln Vivo |
In a xenograft mouse model bearing HL-60 human AML cells, intraperitoneal administration of Remetinostat at doses of 25 mg/kg and 50 mg/kg twice daily for 14 days significantly suppressed tumor growth by 42% and 68%, respectively, compared to the vehicle control group [1]
- Tumor tissues from Remetinostat-treated mice showed increased acetylation of histone H3 and reduced Ki-67 proliferation index, as confirmed by immunohistochemical staining [1] |
| Enzyme Assay |
Recombinant HDAC enzymes (HDAC1, HDAC2, HDAC3, HDAC6, HDAC8) were diluted in assay buffer containing Tris-HCl, NaCl, and DTT to a final concentration of 10 nM. Remetinostat was serially diluted in DMSO and added to the enzyme mixture, followed by incubation at 37°C for 30 minutes. A fluorogenic HDAC substrate was then added, and the reaction was allowed to proceed for another 60 minutes at 37°C. The fluorescence intensity was measured using a microplate reader at excitation and emission wavelengths of 360 nm and 460 nm, respectively. IC50 values were calculated by fitting the dose-response curves using nonlinear regression analysis [1]
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| Cell Assay |
HL-60 and MCF-7 cells were seeded in 96-well plates at a density of 5×103 cells per well and incubated overnight at 37°C in a 5% CO2 atmosphere. Remetinostat was serially diluted in culture medium (with DMSO concentration ≤0.1%) and added to the cells, which were then incubated for 72 hours. Cell viability was assessed using a colorimetric assay based on the reduction of a tetrazolium salt; the absorbance was measured at 570 nm, and IC50 values were determined from dose-response curves [1]
- For western blot analysis, HL-60 cells were treated with Remetinostat at concentrations of 0.25 μM, 0.5 μM, 1 μM, and 2 μM for 24 hours. Cells were lysed in RIPA buffer containing protease and phosphatase inhibitors, and protein concentrations were quantified using a bicinchoninic acid assay. Equal amounts of protein were separated by SDS-PAGE, transferred to PVDF membranes, and probed with primary antibodies against acetyl-histone H3 (Lys9), α-tubulin, acetyl-α-tubulin, p21WAF1/CIP1, cyclin D1, and GAPDH (loading control). Horseradish peroxidase-conjugated secondary antibodies were used, and immunoreactive bands were visualized using an enhanced chemiluminescence detection system [1] - PCR analysis was performed on MCF-7 cells treated with Remetinostat (1 μM) for 24 hours. Total RNA was extracted using a phenol-chloroform method, and complementary DNA (cDNA) was synthesized from 1 μg of total RNA using reverse transcriptase and random primers. Quantitative real-time PCR was conducted with specific primers for p21WAF1/CIP1, cyclin D1, and GAPDH (reference gene) using a SYBR Green master mix. Relative gene expression levels were calculated using the 2-ΔΔCt method [1] |
| Animal Protocol |
Female nude mice (6-8 weeks old) were subcutaneously inoculated with 2×106 HL-60 cells suspended in Matrigel at the right flank. When tumors reached a volume of approximately 100 mm3, mice were randomly divided into three groups (n=6 per group): vehicle control group, low-dose Remetinostat group (25 mg/kg), and high-dose Remetinostat group (50 mg/kg). Remetinostat was dissolved in a vehicle consisting of 10% DMSO, 40% polyethylene glycol 400, and 50% saline. The drug was administered intraperitoneally twice daily (every 12 hours) for 14 consecutive days. Tumor volume was measured every other day using a caliper, and tumor volume was calculated using the formula: V = (length × width2)/2. Body weight was recorded weekly to monitor general toxicity [1]
- At the end of the treatment period, mice were euthanized, and tumors were excised, weighed, and fixed in 10% formalin for immunohistochemical analysis. Major organs (liver, kidney, spleen, heart, lungs) were also collected and fixed for histopathological examination [1] |
| ADME/Pharmacokinetics |
After intravenous injection of 10 mg/kg of retemetanovite into Sprague-Dawley rats, the plasma clearance (CL) was 15.2 mL/min/kg, the steady-state volume of distribution (Vss) was 0.85 L/kg, and the terminal half-life (t1/2) was 45 minutes [1]. After oral administration of 50 mg/kg of retemetanovite to rats, the oral bioavailability (F) was 12.3%, the maximum plasma concentration (Cmax) was 0.38 μg/mL, and the time to peak concentration (Tmax) was 1.5 hours [1]. In vitro metabolic stability studies showed that the half-life of retemetanovite in rat liver microsomes was 32 minutes, and the main metabolites were hydroxylated derivatives and deacetylated products [1].
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| Toxicity/Toxicokinetics |
In a 14-day repeated-dose toxicity study in rats, intraperitoneal injection of remetinostat at doses up to 50 mg/kg twice daily did not cause significant changes in body weight, food intake, or hematological parameters (erythrocytes, leukocytes, platelets). No histopathological abnormalities were observed in the liver, kidneys, heart, lungs, and spleen [1]. The plasma protein binding rate of remetinostat in rat plasma was 89.5% and that in human plasma was 91.2% [1].
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| References | |
| Additional Infomation |
Remetinostat is being investigated in the clinical trial NCT02213861 (SHAPE study on the efficacy, safety, and tolerability of stage IA, IB, or IIA cutaneous T-cell lymphoma). Remetinostat is a topical formulation containing a histone deacetylase (HDAC) inhibitor with potential antitumor activity. After transdermal administration, SHP-141 selectively binds to and inhibits HDAC, leading to the accumulation of highly acetylated histones in the skin (dermis and epidermis), inducing chromatin remodeling, and selectively transcribing tumor suppressor genes. These events may result in inhibition of tumor cell division and induce tumor cell apoptosis. HDAC is upregulated in various tumor cell types and is a class of metalloenzymes responsible for histone deacetylation of chromatin. Topical application of SHP-141 allows for high local drug concentrations while minimizing systemic toxicity. Remetinostat (SHP-141) is a soft histone deacetylase inhibitor designed to minimize systemic toxicity through metabolic activation and rapid clearance. Its structure combines a methylparaben moiety with an octanoyl hydroxamic acid group, the latter responsible for HDAC inhibitory activity. This soft drug design aims to improve the therapeutic index by reducing off-target effects and enhancing tissue-specific activity, especially in cancer cells where HDAC overexpression is common [1].
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| Molecular Formula |
C16H21NO6
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| Molecular Weight |
323.35
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| Exact Mass |
323.137
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| Elemental Analysis |
C, 59.43; H, 6.55; N, 4.33; O, 29.69
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| CAS # |
946150-57-8
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| Related CAS # |
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| PubChem CID |
24875489
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| Appearance |
White to off-white solid powder
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| LogP |
2.615
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
23
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| Complexity |
390
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C=CC(OC(CCCCCCC(NO)=O)=O)=CC=1)OC
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| InChi Key |
XDZAHHULFQIBFE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H21NO6/c1-22-16(20)12-8-10-13(11-9-12)23-15(19)7-5-3-2-4-6-14(18)17-21/h8-11,21H,2-7H2,1H3,(H,17,18)
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| Chemical Name |
methyl 4-[8-(hydroxyamino)-8-oxooctanoyl]oxybenzoate
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (7.73 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (7.73 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 25.0 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: ≥ 2.5 mg/mL (7.73 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 | 3.0926 mL | 15.4631 mL | 30.9262 mL | |
| 5 mM | 0.6185 mL | 3.0926 mL | 6.1852 mL | |
| 10 mM | 0.3093 mL | 1.5463 mL | 3.0926 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03875859 | Terminated | Drug: Remetinostat | Squamous Cell Carcinoma | Kavita Sarin | December 12, 2019 | Phase 2 |
| NCT03180528 | Completed | Drug: Remetinostat | Skin Basal Cell Carcinoma | Kavita Sarin | July 7, 2018 | Phase 2 |
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