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Purity: ≥98%
Domatinostat (formerly known as 4SC-202) is a novel class I HDAC inhibitor (HDACi) that potently inhibited survival and proliferation of primary human colon cancer cells and established CRC lines (HT-29, HCT-116, HT-15, and DLD-1). It has IC50 values of 1.20 μM, 1.12 μM, and 0.57 μM for HDAC1, HDAC2, and HDAC3, respectively. Additionally, dominatinostat exhibits inhibitory activity against LSD1, or lysine specific demethylase 1. CRC cells were exposed to 4SC-202, which induced apoptosis activation; however, the cytotoxicity of 4SC-202 was considerably reduced in CRC cells by caspase inhibitors (z-VAD-CHO and z-DVED-CHO). Concurrently, 4SC-202 caused a significant G2-M arrest in CRC cells. AKT activation may be a significant resistance factor for 4SC-202, according to more research. The cytotoxicity of 4SC-202 was significantly enhanced in CRC cells by serum starvation, AKT inhibition (with perifosine or MK-2206), or AKT1-shRNA knockdown. Conversely, in HT-29 cells, constitutively active AKT1 (CA-AKT1) expressed exogenously reduced sensitivity by 4SC-202. Notably, 4SC-202 increased in vitro anti-CRC activity induced by oxaliplatin at a low concentration. We demonstrated that oral gavage of 4SC-202 inhibited HT-29 xenograft growth in nude mice in vivo, and that its activity was enhanced when combined with oxaliplatin. All of these pre-clinical findings suggest that 4SC-202 could be a worthwhile anti-CRC medication and chemoadjuvant that is worth more research.
| Targets |
HDAC-3 ( IC50 = 0.57 μM ); HDAC-2 ( IC50 = 1.12 μM ); HDAC-1 ( IC50 = 1.2 μM ); HDAC-11 ( IC50 = 9.7 μM ); HDAC-5 ( IC50 = 11.3 μM ); HDAC-10 ( IC50 = 21 μM ); HDAC-9 ( IC50 = 50 μM )
Domatinostat tosylate suppresses clonogenic growth, induces caspase activity, and dramatically decreases the proliferation of all epithelial and mesenchymal UC cell lines (IC50 0.15-0.51 μM)[1]. In colorectal cancer (CRC) cells, domatinostat tosylate activates apoptosis, but caspase inhibitors (z-VAD-CHO and z-DVED-CHO) dramatically reduce the cytotoxicity that domatinostat tosylate causes in CRC cells. In the meantime, CRC cells experience a sharp G2-M arrest due to domatinostat tosylate. Additional research indicates that AKT activation may be a significant Domatinostat tosylate resistance factor. The cytotoxicity of domatinostat tosylate is significantly enhanced in colorectal cancer cells by serum starvation, AKT inhibition (with perifosine or MK-2206), or AKT1-shRNA knockdown. In contrast, constitutively active AKT1 (CA-AKT1) expressed exogenously reduces the HT-29 cells' sensitivity to dometinostat tosylate. Notably, oxaliplatin-induced in vitro anti-CRC activity is enhanced by domatinostat tosylate at low concentrations[2]. Strong cytotoxic and proliferation-inhibitory effects are induced against patient-derived primary HCC cells as well as established HCC cell lines (HepG2, HepB3, SMMC-7721) by domatinosal tosylate treatment. Apoptosis signal-regulating kinase 1 (ASK1) is activated by domatinostat tosylate, which results in its translocation to mitochondria and physical association with Cyp-D[3]. |
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| ln Vitro |
Domatinostat tosylate suppresses clonogenic growth, induces caspase activity, and dramatically decreases the proliferation of all epithelial and mesenchymal UC cell lines (IC50 0.15-0.51 μM)[1]. In colorectal cancer (CRC) cells, domatinostat tosylate activates apoptosis, but caspase inhibitors (z-VAD-CHO and z-DVED-CHO) dramatically reduce the cytotoxicity that domatinostat tosylate causes in CRC cells. In the meantime, CRC cells experience a sharp G2-M arrest due to domatinostat tosylate. Additional research indicates that AKT activation may be a significant Domatinostat tosylate resistance factor. The cytotoxicity of domatinostat tosylate is significantly enhanced in colorectal cancer cells by serum starvation, AKT inhibition (with perifosine or MK-2206), or AKT1-shRNA knockdown. In contrast, constitutively active AKT1 (CA-AKT1) expressed exogenously reduces the HT-29 cells' sensitivity to dometinostat tosylate. Notably, oxaliplatin-induced in vitro anti-CRC activity is enhanced by domatinostat tosylate at low concentrations[2]. Strong cytotoxic and proliferation-inhibitory effects are induced against patient-derived primary HCC cells as well as established HCC cell lines (HepG2, HepB3, SMMC-7721) by domatinosal tosylate treatment. Apoptosis signal-regulating kinase 1 (ASK1) is activated by domatinostat tosylate, which results in its translocation to mitochondria and physical association with Cyp-D[3].
Resminostat inhibits proliferation in multiple myeloma (MM) cell lines (OPM-2, NCI-H929, RPMI-8226, U266) with IC50 values in the low micromolar range (e.g., 2.5–3 µmol/L in 3 out of 4 cell lines). It induces apoptosis (up to 93% annexin-V positive cells at 10 µmol/L) and G0/G1 cell cycle arrest at 1 µmol/L in 3 out of 4 cell lines. This is accompanied by downregulation of cyclin D1, Cdc25A, Cdk4, and pRb, and upregulation of p21. It also decreases phosphorylation of 4E-BP1 and p7056k (Akt/mTOR pathway downstream), increases pro-apoptotic proteins Bim and Bax, and decreases anti-apoptotic Bcl-xL. Caspase-3, -8, and -9 are activated. Synergistic effects are observed in combination with melphalan, bortezomib, and the proteasome inhibitor S-2209. [3] |
| ln Vivo |
Domatinostat tosylate, when administered orally, inhibits the growth of HT-29 xenografts in nude mice. This effect is enhanced when oxaliplatin is added[2].
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| Enzyme Assay |
The inhibitory activity of resminostat hydrochloride against recombinant HDAC enzymes (1, 3, 6, 8) was determined using a fluorogenic assay. Enzymes were expressed in mammalian or insect cells with a C-terminal FLAG tag. Enzyme activity was measured by incubating the enzyme with a peptide substrate (Ac-NH-GGK(Ac)-AMC for HDAC1, 3, 6; Ac-RHK(Ac)K(Ac)-AMC for HDAC8) and varying concentrations of the inhibitor in a buffer. After incubation (120-180 min at 30°C), the reaction was stopped with a solution containing trypsin and trichostatin A. The fluorescence of the released AMC group was measured. IC50 values were calculated by setting the activity in wells without inhibitor as 100% and in wells with trichostatin A as 0%. For HDAC1 kinetics, the substrate concentration was varied, and data were analyzed using Lineweaver-Burk plots to determine the Ki value and binding mode. [3]
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| Cell Assay |
Cell Growth/Proliferation:Cell growth was assessed using a WST-1 assay. Cells were seeded and incubated with increasing concentrations of resminostat for 48 or 96 hours. The WST-1 reagent was added, and after 2 hours, absorbance was measured at 450 nm. [3]
Apoptosis Assay: Cells were incubated with resminostat for 48 hours, washed, and stained with annexin-V-FITC and propidium iodide (PI). Apoptosis was quantified by flow cytometry. [3] Cell Cycle Analysis: After drug treatment, cells were harvested, fixed in ethanol, treated with RNase A and PI, and analyzed by flow cytometry to determine DNA content and cell cycle distribution. [3] Western Blot Analysis: Treated cells were lysed, proteins were separated by SDS-PAGE, transferred to membranes, blocked, and incubated with primary antibodies overnight. After washing, membranes were incubated with peroxidase-conjugated secondary antibodies, and signals were detected by chemiluminescence. [3] BrdU Proliferation Assay: Cells were seeded in 96-well plates, treated with resminostat for approximately 57 hours, then labeled with BrdU for 15 hours. Cells were fixed, DNA was denatured, and incorporated BrdU was detected using an anti-BrdU-POD antibody and a colorimetric substrate. Absorbance was measured at 450 nm. [3] |
| Toxicity/Toxicokinetics |
The provided text does not describe specific toxicity or toxicokinetic data for resminostat. It only mentions that significant toxicity has been commonly reported in early clinical trials of HDAC inhibitors, highlighting the need to develop drugs with lower toxicity. [3]
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| References | |
| Additional Infomation |
Resminostat is a novel hydroxamic acid histone deacetylase (HDAC) inhibitor. Its chemical structure differs from vorinostat in the linker region and hydrophobic cap region. It induces excessive acetylation of histone H4 in myeloma cells. This study provides a theoretical basis for integrating HDAC inhibitors such as resminostat into multidrug combination therapy regimens for multiple myeloma, especially when used in combination with proteasome inhibitors. [3]
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| Molecular Formula |
C₃₀H₂₉N₅O₆S₂
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| Molecular Weight |
619.71
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| Exact Mass |
619.155
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| CAS # |
1186222-89-8
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| Related CAS # |
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| PubChem CID |
44217246
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| Appearance |
Light yellow to brown solid powder
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| LogP |
7.417
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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 |
7
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| Heavy Atom Count |
43
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| Complexity |
981
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CN1C=C(C=N1)C2=CC=C(C=C2)S(=O)(=O)N3C=CC(=C3)/C=C/C(=O)NC4=CC=CC=C4N
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| InChi Key |
IAVXAZDVNICKFJ-ICSBZGNSSA-N
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| InChi Code |
InChI=1S/C23H21N5O3S.C7H8O3S/c1-27-16-19(14-25-27)18-7-9-20(10-8-18)32(30,31)28-13-12-17(15-28)6-11-23(29)26-22-5-3-2-4-21(22)24;1-6-2-4-7(5-3-6)11(8,9)10/h2-16H,24H2,1H3,(H,26,29);2-5H,1H3,(H,8,9,10)/b11-6+;
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| Chemical Name |
(E)-N-(2-aminophenyl)-3-[1-[4-(1-methylpyrazol-4-yl)phenyl]sulfonylpyrrol-3-yl]prop-2-enamide;4-methylbenzenesulfonic acid
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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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 (4.03 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 (4.03 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6137 mL | 8.0683 mL | 16.1366 mL | |
| 5 mM | 0.3227 mL | 1.6137 mL | 3.2273 mL | |
| 10 mM | 0.1614 mL | 0.8068 mL | 1.6137 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.
 Impact of specific pharmacological inhibition of class I HDAC isoenzymes with 4SC-202 on UCCs and control cells.Target Oncol.2016 Dec;11(6):783-798. |
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 Morphology, clonogenicity and senescence following 4SC-202 treatment in UCCs and control cells.Target Oncol.2016 Dec;11(6):783-798. |
 Mechanisms of cell death upon 4SC-202 treatment in UCCs and control cells.Target Oncol.2016 Dec;11(6):783-798. |
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