| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg | |||
| 100mg | |||
| 250mg | |||
| 500mg | |||
| Other Sizes |
Purity: ≥98%
SIS17 is a novel, potent and isoform-selective inhibitor of mammalian histone deacetylase 11 (HDAC 11) with an IC50 value of 0.83 μM. SIS17 is active in cells and prevented serine hydroxymethyl transferase 2, a known HDAC11 substrate, from being demyristoylated without interfering with the activity of other HDACs. Other classes of enzymes may benefit from the development of isoform-specific inhibitors through the application of activity-guided design. Enzymes belonging to the class known as mammalian histone deacetylases (HDACs) are crucial components of biological pathways. Current HDAC inhibitors have a limited degree of selectivity and target several HDACs. One-specific HDAC-targeting inhibitors will be helpful in learning more about the biological roles of HDACs and in creating more effective treatments. Although little is known about HDAC11's biological role or enzymatic activity, recent reports indicate that it has effective defatty-acylation activity and that blocking it may be helpful in treating a range of human conditions, such as metabolic disorders, multiple sclerosis, and viral infections.
| Targets |
HDAC11 ( IC50 = 0.83 μM )
SIS17 is a potent and selective inhibitor of Histone Deacetylase 11 (HDAC11). (IC₅₀ = 0.83 µM when measured using a myristoyl-H3K9 peptide as substrate; IC₅₀ = 270 nM when measured using a myristoyl-SHMT2 peptide as substrate). [1] |
|---|---|
| ln Vitro |
In MCF7 cells, SIS17 (0-50 μM, 6 hours) raises the fatty acylation level of SHMT2 [1]. In K562 cells, SIS17 (48 hours) in combination with oxaliplatin demonstrated good cytotoxicity [2].
SIS17 inhibited HDAC11 enzymatic activity in vitro with an IC₅₀ of 0.83 µM using a myristoyl-H3K9 peptide substrate. When tested with a physiological myristoyl-SHMT2 peptide substrate, the potency improved to an IC₅₀ of 270 nM. [1] SIS17 demonstrated high selectivity for HDAC11 over other HDAC isoforms and sirtuins. At a concentration of 100 µM, it did not significantly inhibit Class I HDACs (HDAC1, HDAC8), Class II HDACs (HDAC4), or Class III sirtuins (SIRT1, SIRT2, SIRT3, SIRT6). In contrast, a reference compound FT895 inhibited HDAC4 (IC₅₀ = 25 µM) and HDAC8 (IC₅₀ = 9.2 µM) under the same conditions. [1] SIS17 was designed based on the unique defatty-acylase activity profile of HDAC11. It incorporates a long hydrophobic alkyl chain intended to confer selectivity for HDAC11's preference for long-chain fatty acyl lysine substrates, along with a zinc-chelating hydroxamate group essential for inhibition. [1] |
| Enzyme Assay |
HDAC11 enzymatic activity was measured using an HPLC-based assay. Recombinant HDAC11 was incubated with peptide substrates (either myristoyl-H3K9 or myristoyl-SHMT2) in an appropriate reaction buffer. The reaction was allowed to proceed for a specified time, then quenched. The mixture was analyzed by reverse-phase HPLC to separate and quantify the substrate and product (the deacylated peptide). The percentage of substrate remaining or product formed was calculated to determine enzyme activity. For inhibition assays, various concentrations of SIS17 were pre-incubated with HDAC11 before adding the substrate. IC₅₀ values were determined by plotting the percentage of remaining enzyme activity against the inhibitor concentration. [1]
Selectivity profiling against other HDACs and sirtuins was performed using similar activity assays with their respective characteristic substrates (e.g., acetyl- or trifluoroacetyl-lysine peptides for deacetylase activity, acyl-H3K9 peptides for defatty-acylase activity). SIS17 was tested at a single high concentration (100 µM) against each enzyme to assess selectivity. [1] |
| Cell Assay |
To assess cellular target engagement, MCF7 cells were treated with a palmitic acid analog (Alk14, 50 µM) to metabolically label fatty-acylated proteins. Concurrently, cells were treated with increasing concentrations of SIS17 (0, 12.5, 25.0, 50.0 µM) for 6 hours at 37°C. Cells were then lysed. The alkynetagged proteins were conjugated to a biotin tag via click chemistry and subsequently pulled down using streptavidin beads. The precipitated proteins were analyzed by Western blot using an antibody against SHMT2 to specifically detect the level of fatty-acylated SHMT2. SIS17 treatment significantly increased the fatty acylation level of endogenous SHMT2 in a dose-dependent manner, indicating effective cellular penetration and inhibition of HDAC11 activity. [1]
To confirm cellular selectivity, HEK 293T cells were treated with SIS17 (up to 50 µM) for 6 hours. Cell lysates were then subjected to Western blot analysis using antibodies against acetyl-α-tubulin (K40) and acetyl-histone H3, which are common substrates of other HDACs. SIS17 did not increase the acetylation levels of these proteins, unlike the pan-HDAC inhibitor SAHA, confirming its selective action on HDAC11 within cells. [1] Cell permeability/metabolic stability was inferred from an LC-MS based assay. SIS17 could be detected in cell lysates after treatment, whereas its analog SIS7 could not, suggesting better cellular availability for SIS17. [1] |
| ADME/Pharmacokinetics |
SIS17 was detected in the treated cell lysate using a liquid chromatography-mass spectrometry (LC-MS) method, confirming its ability to enter cells. In contrast, the related inhibitor SIS7 was not detected under the same conditions, indicating that SIS17 has stronger cell permeability and/or metabolic stability. [1]
|
| References | |
| Additional Infomation |
SIS17 was developed using an activity-driven rational design strategy, leveraging the unique hydrolytic preference of HDAC11 for long-chain fatty acyl lysine modification rather than acetyl lysine. [1]
It is reportedly the first selective HDAC11 inhibitor to exhibit cellular effects, specifically enhancing the fatty acylation level of the physiological HDAC11 substrate SHMT2. [1] Inhibition of HDAC11-mediated SHMT2 defatty acylation is thought to regulate type I interferon receptor signaling, suggesting potential therapeutic value in viral infections, multiple sclerosis, and metabolic diseases, although these applications remain speculative in the context of this study. [1] This compound is a valuable chemical tool for further research into the biological functions of HDAC11. [1] |
| Molecular Formula |
C21H38N2OS
|
|---|---|
| Molecular Weight |
366.604224681854
|
| Exact Mass |
366.27
|
| Elemental Analysis |
C, 68.80; H, 10.45; N, 7.64; O, 4.36; S, 8.75
|
| CAS # |
2374313-54-7
|
| PubChem CID |
139035087
|
| Appearance |
White to off-white solid powder
|
| LogP |
8.7
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
3
|
| Rotatable Bond Count |
17
|
| Heavy Atom Count |
25
|
| Complexity |
312
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
HSHXDCVZWHOWCS-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C21H38N2OS/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-18-22-23-21(24)20-17-16-19-25-20/h16-17,19,22H,2-15,18H2,1H3,(H,23,24)
|
| Chemical Name |
N'-hexadecylthiophene-2-carbohydrazide
|
| Synonyms |
SIS17; SIS-17; SIS 17
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product is not stable in solution, please use freshly prepared working solution for optimal results. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO: 73~100 mg/mL (199.1~272.8 mM)
Ethanol: 18 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.67 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 mg/mL (5.46 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 20.0 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 | 2.7278 mL | 13.6388 mL | 27.2777 mL | |
| 5 mM | 0.5456 mL | 2.7278 mL | 5.4555 mL | |
| 10 mM | 0.2728 mL | 1.3639 mL | 2.7278 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.
|
|
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA
