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ITF 3756 is a selective, orally active HDAC6 inhibitor. ITF 3756 antagonizes TNF-α-induced activation of the NF-κB pathway. ITF 3756 reduces PD-L1 expression on human monocytes and CD8+ T cells, and exhibits antitumor activity. ITF 3756 can be used in colon cancer-related research.
ITF 3756 is a selective, orally active HDAC6 inhibitor. ITF 3756 antagonizes TNF-α-induced activation of the NF-κB pathway. ITF 3756 reduces PD-L1 expression on human monocytes and CD8+ T cells, and exhibits antitumor activity. ITF 3756 can be used in colon cancer-related research[1][2][3].
Inhibition of recombinant full length human N-terminal GST-tagged HDAC6 expressed in baculovirus infected sf9 insect cells pretreated with compound followed by Fluor de Lys deacetylase substrate addition by fluorescence method
Inhibition of recombinant full length human N-terminal GST-tagged HDAC6 expressed in baculovirus infected sf9 insect cells pretreated with compound followed by Fluor de Lys deacetylase substrate addition by fluorescence method
ITF 3756 (6 h) downregulates the expression of TNF-α-induced activation and differentiation markers by regulating the expression of specific genes, and induces a phenotype with weaker immunosuppressive properties in purified human monocytes[1]. ITF3756 (0.06-1.5 μM; 4-20 h) downregulates PD-L1 expression in a dose- and time-dependent manner, attenuates the immunosuppressive phenotype of primary human monocytes stimulated with TNF-α, and promotes the costimulatory phenotype by upregulating CD40 expression, with no cytotoxicity observed at the tested concentrations[2]. ITF3756 (1 μM; 3-6 h) upregulates CD40 gene expression and downregulates PD-L1 gene expression in TNF-α-stimulated primary human monocytes, with a significant effect on PD-L1 observed at 4 hours post-stimulation[2]. ITF3756 (1 μM; overnight) downregulates PD-L1 expression on TNF-α-stimulated primary human monocytes derived from patients with colorectal cancer and breast cancer, which is consistent with the effect observed in monocytes from healthy donors[2] ITF3756 (1 μM; 6 h) inhibits the TNF-α, NF-κB and NOD-like receptor signaling pathways, downregulates the expression of inhibitory immune checkpoint genes and M2 macrophage markers, and upregulates metabolic pathways in primary human monocytes stimulated with TNF-α, thereby inducing their transition to a phenotype with weaker immunosuppression and stronger metabolic activity[2]. ITF3756 (1 μM; 19 h) downregulates the expression of proteins related to antigen presentation, inflammatory signaling pathways and cell death in primary human monocytes stimulated by TNF-α, while upregulating the expression of proteins related to metabolic pathways. This is consistent with the results of transcriptomic studies showing that these cells exhibit a phenotype with lower immunosuppression and higher metabolic activity[2]. ITF3756 (1 μM; 2.15 h) inhibits TNF-α-induced activation of the NF-κB pathway in primary human monocytes by reducing the phosphorylation level of p65 at the Ser536 site[2]. ITF3756 (1 μM; 6 d) enhances the capacity of TNF-α-stimulated primary human monocytes to activate allogeneic T cells; this effect is reflected by increased T cell proliferation levels in MLR assays and produces a synergistic effect when combined with anti-PD-L1 antibodies[2]. ITF3756 (0.5-1 μM; 5 d) enhances the antigen-presenting cell phenotype of monocyte-derived iDCs and mDCs by upregulating CD86 expression while slightly downregulating PD-L1 expression[2]. ITF3756 (1 μM; 10 d) enhances the ability of monocyte-derived iDCs to activate allogeneic T cells, which is confirmed by the increased T cell proliferation observed in mixed lymphocyte reaction (MLR) assays[2]. ITF3756 (1-10 μM; 48 h) reduces the viability of HCT116 colon cancer cells in a dose-dependent manner. After 48 h of treatment, cell viability decreases by approximately 50% at 5 μM, and is almost completely lost at 10 μM[3]. ITF3756 (1-10 μM; 48 h) reduces the viability of HT29 colon cancer cells in a dose-dependent manner. After 48 h of treatment, cell viability decreases by approximately 25% at 5 μM and by approximately 50% at 10 μM[3]. ITF3756 (2-7 μM; 48 h) promotes lipid accumulation in HCT116 colon cancer cells in a dose-dependent manner within 48 h, with a significant increase in lipid droplet formation observed at 7 μM[3]. ITF3756 (2-7 μM; 48 h) dose-dependently increases lipid accumulation in HT29 colon cancer cells, with an action duration exceeding 48 h, and the accumulation levels are significantly elevated at concentrations of 5 μM and 7 μM[3]. ITF3756 (2 μM; 48 h) selectively inhibits HDAC6 activity in HCT116 colon cancer cells for a duration exceeding 48 h, which is evidenced by increased levels of α-acetylated tubulin[3]. Treatment with ITF3756 (2 μM; 48 h) alone exerts mild, subtoxic cytostatic effects on HCT116 colon cancer cells within 48 h[3]. ITF3756 (2 μM; 48 h) alone exerts mild subtoxic effects on the viability of HT29 colon cancer cells within 48 h[3]. ITF3756 (2 μM; 24-48 h) alone slightly increases p53 levels in HCT116 colon cancer cells within 24-48 h, but does not activate apoptotic markers[3]. Treatment with ITF3756 (2 μM; 24 h) alone induces mild lipogenic activity in HCT116 colon cancer cells within 24 h, which is evidenced by a moderate increase in the levels of cleaved SREBP-1 and PPAR-γ[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Reduced HCT116 cell viability in a dose-dependent manner. Reduced viability by ~50% at 5 μM relative to untreated controls. Reduced viability to near 0% at 10 μM relative to untreated controls. Induced cell shrinkage and detachment (signs of cell death) at 7 μM.
Reduced HT29 cell viability in a dose-dependent manner. Reduced viability by ~25% at 5 μM relative to untreated controls. Reduced viability by ~50% at 10 μM relative to untreated controls. Reduced cell number but maintained viability at 7 μM.
Produced a faint increase in cleaved SREBP-1 levels relative to untreated controls. Produced a modest increase in PPAR-γ levels relative to untreated controls. Detected a faint band of cleaved SREBP-1 in the nuclear fraction.
2 μM (with 1 h pre-incubation with 7.5 μM DGAT-1i and 10 μM DGAT-2i)
Incubation Time:
24 h; 48 h
Result:
Exacerbated the viability-reducing effect of the 2 μM ITF3756/5 nM bortezomib combination, with further reduced cell viability and increased signs of cell death relative to the combination alone.
2 μM (with 16 h pre-transfection with SREBP-1 siRNA)
Incubation Time:
24 h
Result:
Potentiated the viability-reducing effect of the 2 μM ITF3756/5 nM bortezomib combination in SREBP-1-silenced cells, with greater reduction in cell viability relative to control siRNA-transfected cells.
体内実験
ITF3756 (25-50 mg/kg; oral administration; 1-3 times daily for 14 consecutive days) inhibits tumor growth in the mouse CT26 colon cancer model in a dose- and regimen-dependent manner[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Model:
BALB/c (6-week-old female; subcutaneous injection of 1 x 10^6 CT26 tumor cells)[2]
Dosage:
25 mg/kg (BID, TID); 50 mg/kg (QD, BID, TID)
Administration:
oral gavage; twice a day (BID); three times a day (TID); once a day (QD) for 14 days
Result:
Achieved significant tumor growth inhibition starting at day 17 post-transplant, with a maximum 46% inhibition by study end (25 mg/kg TID). Achieved significant tumor growth inhibition observed at day 19 and 24 post-transplant, with a maximum 31% inhibition (25 mg/kg BID). Achieved significant tumor growth inhibition starting at day 17 post-transplant, with maximum inhibition of 52% (BID) and 55% (TID) by study end (50 mg/kg). Achieved significant tumor growth inhibition observed at day 19 and 24 post-transplant, with a maximum 27% inhibition (50 mg/kg QD).
Room temperature in continental US; may vary elsewhere.
保管条件
Powder
-20°C
3 years
4°C
2 years
In solvent
-80°C
6 months
-20°C
1 month
溶剤 & 溶解度
体外:
DMSO : 125 mg/mL (414.84 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Preparing Stock Solutions
ConcentrationSolventMass
1 mg
5 mg
10 mg
1 mM
3.3187 mL
16.5937 mL
33.1873 mL
5 mM
0.6637 mL
3.3187 mL
6.6375 mL
10 mM
0.3319 mL
1.6594 mL
3.3187 mL
View the Complete Stock Solution Preparation Table
*Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles. Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for in vivo experiments, it is recommended to prepare freshly and use it on the same day. The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.
This protocol yields a clear solution of ≥ 2.08 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μLDMSO stock solution (20.8 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
Protocol 2
Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in Saline)
This protocol yields a clear solution of ≥ 2.08 mg/mL (saturation unknown). If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Taking 1 mL working solution as an example, add 100 μLDMSO stock solution (20.8 mg/mL) to 900 μLCorn oil, and mix evenly.
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:
Dosage
mg/kg
Animal weight (per animal)
g
Dosing volume (per animal)
μL
Number of animals
Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
%
DMSO+
%
+
%
Tween-80
+
%
Saline
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
The co-solvents required include: DMSO,
. All of co-solvents are available by MedChemExpress (MCE).
, Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Calculation results:
Working solution concentration:
mg/mL
Method for preparing stock solution:
mg
drug dissolved in
μL
DMSO (Stock solution concentration: mg/mL).
The concentration of the stock solution you require exceeds the measured solubility. The following solution is for reference only. If necessary, please contact MedChemExpress (MCE).
Method for preparing in vivo working solution for animal experiments: Take
μL DMSO stock solution, add
μL .
μL , mix evenly, next add
μL Tween 80, mix evenly, then add
μL Saline.
Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution
If the continuous dosing period exceeds half a month, please choose this protocol carefully.
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
*Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles. Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.
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