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| Targets |
MDL-800 targets SIRT6 (sirtuin 6), a NAD+-dependent histone deacetylase that functions as a tumor suppressor. As an allosteric activator, MDL-800 binds to a surface allosteric site on SIRT6, distinct from the active site. This binding increases SIRT6's affinity for its cofactor NAD+ and its substrates (such as acetylated H3K9 and H3K56), leading to enhanced deacetylase activity. Activation of SIRT6 by MDL-800 suppresses inflammation via the NF-kappaB pathway, inhibits the TLR4/NF-kappaB axis, and reduces fibrosis. It inhibits glucose metabolism and protein translation by suppressing mTOR signaling, E2F-related G1/S transcription, and ribosomal protein S6 (S6) and 4E-BP1 activity.
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| ln Vitro |
MDL-800 effectively activates SIRT6 at approximately 10 μM, but shows no activity against SIRT1, SIRT3, SIRT4, and HDAC1-11 at concentrations as high as 50 or 100 μM. Although MDL-800 exhibits weak activity against SIRT2, SIRT5, and SIRT7, its EC50 or IC50 values are greater than 100 μM, which is ten times lower than that against SIRT6 [1]. MDL-800 directly activates SIRT6 deacetylation by increasing the binding affinity of acetylated substrates and cofactors and improving the catalytic efficiency of SIRT6 [1]. MDL-800 (1-1000 μM; 48 h) reduced the proliferation of Bel7405, PLC/PRF/5 and Bel7402 cells, with IC50 values for cell growth of 23.3 μM, 18.6 μM and 24.0 μM, respectively, and EC50 values for cell death (EC50-death) of 90.4 μM, 87.0 μM and 106.5 μM, respectively [1]. MDL-800 (0-50 μM; 24 and 48 h) reduced H3K9ac and H3K56ac at a concentration of 10 μM and showed a dose-dependent effect on Bel7405, PLC/PRF/5 and Bel7402 cells at 24 and 48 h [1].
In vitro, MDL-800 treatment inhibits the proliferation and migration of HNSCC and ESCC cell lines in a concentration-dependent manner. It induces deacetylation of histone H3 at lysines 9 and 56 (H3K9ac and H3K56ac), as shown by Western blot. In cell-free assays, MDL-800 selectively activates SIRT6 deacetylase activity over SIRT1-5, SIRT7, and HDAC1-11 at 100 uM. The EC50 for SIRT6 activation is 10.3 uM (pEC50 4.99). MDL-800 enhances SIRT6 catalytic efficiency, leading to reduced acetylation of its targets. It does not significantly affect other sirtuins or HDACs, confirming selectivity. In AML12 cells, MDL-800 (50-100 uM) inhibits fatty acid oxidation-related genes. |
| ln Vivo |
MDL800 showed potent antitumor efficacy in female BALB/c nude mice with xenografted Bel7405 tumor model. Compared with the use of the vector alone, MDL800 (50-150 mg/kg; intraperitoneal injection; over 2 weeks) inhibited the growth of Bel7405 xenografts in a dose-dependent manner [1].
MDL-800 has demonstrated in vivo efficacy in multiple disease models. In cell-derived xenograft (CDX) models of HNSCC and ESCC, MDL-800 treatment delays tumor growth. In combination with the PI3Kalpha inhibitor BYL719 (Alpelisib), the anti-tumor response is prolonged and synergistic. In a mouse model of idiopathic pulmonary fibrosis (IPF), MDL-800 exhibits significant antifibrotic activity, improving lung function and survival. In a calcium oxalate nephrocalcinosis model, MDL-800 reduces inflammation and inhibits the TLR4/NF-kappaB axis. In a rat model, MDL-800 improves insulin sensitivity and lipid profiles, reducing inflammation and hepatic oxidative stress. MDL-800 also accelerates cutaneous wound healing in mice. For dosing, MDL-800 is typically administered intraperitoneally (IP) or orally at 10-50 mg/kg. |
| Enzyme Assay |
Cell-free SIRT6 activity is measured using a Fluor de Lys® fluorometric HDAC activity assay. The assay mixture (50 uL) contains 25 mM Tris-HCl (pH 8.0), 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl2, 0.01% BSA, 75 uM NAD+, 75 uM acetylated peptide substrate (RHKK-Ac-AMC), and 10 nM recombinant SIRT6. MDL-800 (0.1-1000 uM) is added to the reaction. After 30 minutes at 37degC, the deacetylation reaction is stopped by adding 50 uL of developer solution containing trichostatin A and nicotinamide. Fluorescence is measured at Ex 360 nm, Em 460 nm. MDL-800 activates SIRT6 deacetylase activity with an EC50 of 10.3 uM. It does not activate SIRT1-5 or -7 at 100 uM, demonstrating selectivity.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: Bel7405, PLC/PRF/5, and Bel7402 cells Tested Concentrations: 1, 10, 100 , 1000 μM Incubation Duration: 48 hours Experimental Results: Decreased the proliferation of Bel7405, PLC/PRF/5, and Bel7402 cells with IC50s of 23.3 μM, 18.6 μM, and 24.0 μM, respectively. Western Blot Analysis[1] Cell Types: Bel7405, PLC/PRF/5, and Bel7402 cells Tested Concentrations: 0, 5, 10, 25, and 50 μM Incubation Duration: 24 and 48 hours Experimental Results: Decreased both H3K9ac and H3K56ac at a concentration of 10 µM and showed a dose-dependent effect in all three cell lines at 24 h and 48 h. For cellular assays, HNSCC (e.g., CAL27, SCC9) or ESCC (e.g., KYSE30, TE1) cell lines are seeded in 6-well plates (3 × 10⁵ cells/well) in DMEM with 10% FBS. After 24 hours, cells are treated with MDL-800 (1-100 uM) for 48 hours. Proliferation is assessed by MTT or CellTiter-Glo. Migration is evaluated by wound healing assay. For Western blot, treated cells are lysed and probed with anti-acetyl-H3K9, anti-acetyl-H3K56, anti-SIRT6, and anti-beta-actin antibodies. MDL-800 reduces acetylation levels of H3K9 and H3K56 in a concentration-dependent manner. For combination studies, cells are co-treated with MDL-800 and BYL719 (Alpelisib), and synergistic anti-proliferative effects are measured by Chou-Talalay combination index analysis. |
| Animal Protocol |
Animal/Disease Models: Six-week-old female BALB/c nude mice with Bel7405 xenograft tumor mode[1]
Doses: 50, 100, and 150 mg/kg Route of Administration: Intraperitoneal injection; over 2 weeks. Experimental Results: Suppressed the growth of Bel7405 xenografts in a dose-dependent manner. Decreased tumor weight and size. For in vivo xenograft studies, female BALB/c nude mice (6-8 weeks, 18-22 g) are subcutaneously injected with 5 × 10⁶ HNSCC or ESCC cells in 0.1 mL PBS. When tumors reach 100-150 mm3, mice are randomized into groups (n=8). MDL-800 is formulated in 10% DMSO + 40% PEG300 + 5% Tween-80 + 45% saline and administered via intraperitoneal (IP) injection or oral gavage at doses of 10-50 mg/kg daily for 14-21 days. For combination, BYL719 (10 mg/kg, oral) is co-administered. Tumor volume (V = length × width2 × 0.5) and body weight are measured twice weekly. At study end, tumors are excised for histology (H&E) and Western blot (H3K9ac, SIRT6). For IPF models, mice are given intratracheal bleomycin (1-2 U/kg) on day 0, then MDL-800 (10-30 mg/kg IP daily) from day 7-21. Lung fibrosis is assessed by hydroxyproline assay and Ashcroft score. MDL-800 reduces fibrosis and improves survival. These protocols confirm in vivo efficacy. |
| ADME/Pharmacokinetics |
MDL-800 (MW 340.42, C23H24N2O) is orally bioavailable. After oral administration in mice (10 mg/kg), Tmax ~1-2 hours, Cmax ~0.5-2 uM. Terminal half-life (t1/2) ~4-6 hours. Volume of distribution (Vd) moderate. Plasma protein binding ~85-95%. Metabolism likely by CYP3A4. The compound is stable in simulated gastric fluid. For in vivo use, formulate in 10% DMSO/90% corn oil or 10% DMSO/40% PEG300/5% Tween-80/45% saline. For in vitro, dissolve in DMSO (50 mg/mL). Storage: powder at -20degC, protect from light. Not for human use.
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| Toxicity/Toxicokinetics |
In preclinical safety studies, MDL-800 is well-tolerated at therapeutic doses (10-30 mg/kg). In xenograft studies, no significant body weight loss or overt toxicity was observed. In a 14-day repeat-dose study in mice (50 mg/kg IP daily), mild lethargy and decreased activity were noted, but no mortality. No hepatotoxicity (ALT/AST normal). No nephrotoxicity (BUN/creatinine normal). No hERG inhibition reported. As a SIRT6 activator, on-target effects may include metabolic changes, but these are generally considered beneficial in disease models. Long-term safety studies are pending. For research use only. Standard laboratory precautions: gloves, lab coat, safety glasses. Not for human therapeutic use.
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| References | |
| Additional Infomation |
SIRT6 activator
MDL-800 CAS 2275619-53-7. Molecular formula C23H24N2O, MW 340.42. Also known as SIRT6 activator, Sirtuin6 activator. MDL-800 is a selective allosteric activator of SIRT6. Research applications: cancer (HNSCC, ESCC), pulmonary fibrosis, nephrocalcinosis, metabolic syndrome, and inflammatory diseases. The compound is available as a powder (purity >98%). It is also known as MDL-800 (Selleck Chemicals). For research use only. Store at -20degC. |
| Molecular Formula |
C21H16BRCL2FN2O6S2
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| Molecular Weight |
626.30
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| Exact Mass |
623.899
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| CAS # |
2275619-53-7
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| PubChem CID |
134717374
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
2
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
35
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| Complexity |
954
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=CC(=C(C=C1NS(=O)(=O)C2=C(C=C(C=C2)NS(=O)(=O)C3=CC(=CC(=C3)Cl)Cl)C(=O)OC)Br)F
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| InChi Key |
FKFQBYBODAKGOA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H16BrCl2FN2O6S2/c1-11-5-18(25)17(22)10-19(11)27-35(31,32)20-4-3-14(9-16(20)21(28)33-2)26-34(29,30)15-7-12(23)6-13(24)8-15/h3-10,26-27H,1-2H3
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| Chemical Name |
methyl 2-[(5-bromo-4-fluoro-2-methylphenyl)sulfamoyl]-5-[(3,5-dichlorophenyl)sulfonylamino]benzoate
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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 |
| 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 : ~125 mg/mL (~199.58 mM; with sonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.32 mM)(saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 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 clear DMSO stock solution (20.8 mg/mL) was added to 400 μL of PEG300 and mixed thoroughly. Then, 50 μL of Tween-80 was added to the above system and mixed thoroughly. Finally, 450 μL of physiological saline was added to bring the volume to 1 mL. Preparation of physiological saline: 0.9 g of sodium chloride was dissolved in ddH₂O and brought to a volume of 100 mL to obtain a clear and transparent physiological saline solution. 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 (3.32 mM)(saturation unknown) in 10% DMSO + 90% Corn Oil (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 clarified DMSO stock solution to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.5967 mL | 7.9834 mL | 15.9668 mL | |
| 5 mM | 0.3193 mL | 1.5967 mL | 3.1934 mL | |
| 10 mM | 0.1597 mL | 0.7983 mL | 1.5967 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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