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| Targets |
The primary targets of AES-135 are histone deacetylases (HDACs), specifically HDAC3, HDAC6, HDAC8, and HDAC11. HDACs are enzymes that remove acetyl groups from histone proteins, leading to chromatin condensation and transcriptional repression. By inhibiting HDACs, AES-135 promotes histone acetylation, leading to the activation of tumor suppressor genes and the induction of apoptosis in cancer cells. The compound's hydroxamic acid moiety chelates the zinc ion in the HDAC active site, leading to reversible inhibition. Its activity against multiple HDAC isoforms contributes to its broad anti-tumor effects.
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| ln Vitro |
AES-135 prevents cancer cells from proliferating. BT189, D425, D458, MV4, BT143, and 1.4 µM, 0.27 µM, 0.94 µM, 1.9 µM, 2.72 µM, 2.1 µM, 15.0 µM, 1.6 µM, and 19.2 µM are the IC50 values of these compounds. These cells are called MRC-9, -11, PC-3, MDA-MB-231, MOLM-13, and K562 [1].
In vitro, AES-135 exhibits nanomolar inhibitory activity against HDAC3, HDAC6, and HDAC11. It inhibits HDAC3 with an IC50 of 654 nM, HDAC6 with an IC50 of 190 nM, and HDAC11 with an IC50 of 636 nM. It also inhibits HDAC8 with an IC50 of 1100 nM. The compound's inhibitory activity is concentration-dependent, with effects observed at nanomolar to micromolar concentrations. In a three-dimensional coculture model, AES-135 kills low-passage patient-derived cancer cells. Its ability to inhibit multiple HDAC isoforms makes it a valuable tool for studying the role of HDACs in cancer biology. |
| ln Vivo |
AES-135 (50 mg/kg; intraperitoneal injection; 5 days per week; for 1 month) treatment significantly enhanced the survival rate of C57Bl/6 mice implanted with KPC2 cells [1]. NSG mice were dosed with a single intraperitoneal (IP) injection of 20 mg/kg, and blood was taken after 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours. AES-135 achieves μM concentrations in blood, achieving a Cmax of 7452 ng/mL (10.74 μM) after 30 minutes and remaining for 8 hours. Blood concentrations of AES-135 were dose-dependent, reaching an average of 323 ng/mL (0.47 μM) at a dose of 10 mg/kg and an average of 1829 ng/mL (2.64 μM) at a dose of 40 mg/kg. AES-135 demonstrates remarkable pharmacokinetic properties in mice, having an in vivo half-life of 5.0 hours [1].
In vivo, AES-135 has been shown to prolong survival in an orthotopic mouse model of pancreatic cancer. The compound achieves micromolar blood levels with a Cmax of approximately 10.7 microM and an in vivo half-life of 5 hours. These pharmacokinetic properties support sustained HDAC inhibition and translational studies in hematologic and solid tumors. AES-135 has excellent pharmacokinetic properties in vivo. Its in vivo efficacy in prolonging survival in an orthotopic model of pancreatic cancer supports its potential as a therapeutic agent for this deadly disease. |
| Enzyme Assay |
The in vitro HDAC inhibition activity of AES-135 can be assessed using cell-free enzyme assays with recombinant HDAC isoforms. A typical protocol involves incubating the HDAC enzyme with a fluorogenic substrate (e.g., Ac-Lys-AMC) and AES-135 at various concentrations in a reaction buffer. The reaction is carried out at 37degC for 30-60 minutes. The deacetylated substrate is then cleaved by a developer to release the fluorophore, and the fluorescence is measured. The IC50 value is determined by plotting the percentage of HDAC activity remaining against the compound concentration. The selectivity of the compound can be assessed by testing its activity against a panel of HDAC isoforms.
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| Cell Assay |
For in vitro cellular experiments, cancer cell lines (e.g., pancreatic cancer cells) are cultured in appropriate media and treated with AES-135 at various concentrations (typically 0.1-100 microM). After treatment, cells are harvested, and histone acetylation levels are assessed by Western blot using antibodies specific for acetylated histones (e.g., acetyl-H3, acetyl-H4). Cell proliferation is measured using MTT or other cell proliferation assays. Apoptosis is assessed by flow cytometry using Annexin V/PI staining or by measuring caspase-3/7 activity. The duration of treatment varies depending on the experimental design but typically ranges from 24 to 72 hours.
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| Animal Protocol |
Animal/Disease Models: C57Bl/6 mice injected with KPC2 cells [1]
Doses: 50 mg/kg Route of Administration: intraperitoneal (ip) injection; 5 days a week; lasted for 1 month. Experimental Results: The survival rate of mice was Dramatically increased. In vivo animal experiments with AES-135 typically involve oral or intraperitoneal administration in mouse models of pancreatic cancer or other tumor types. A common dosing regimen is 10-40 mg/kg. For orthotopic models, cancer cells are implanted directly into the pancreas, and the compound is administered daily. Tumor growth is monitored by bioluminescence imaging or ultrasound. Survival is monitored as the primary endpoint. Pharmacokinetic studies are performed by collecting blood samples at various time points after dosing and measuring plasma drug concentrations by LC-MS/MS. Toxicity studies are also performed to characterize its safety profile. |
| ADME/Pharmacokinetics |
AES-135 has an impressive pharmacokinetic profile in mice. It achieves micromolar blood levels with a Cmax of approximately 10.7 microM and an in vivo half-life of 5 hours. At a dose of 10 mg/kg, it achieves an average Cmax of 323 ng/mL (0.47 microM), and at 40 mg/kg, it achieves 1829 ng/mL (2.64 microM). These pharmacokinetic properties support sustained HDAC inhibition and once-daily dosing. The compound has excellent pharmacokinetic properties in vivo, making it a promising candidate for further development.
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| Toxicity/Toxicokinetics |
AES-135 has been shown to be well-tolerated in preclinical studies. It has excellent pharmacokinetic properties and has been evaluated in an orthotopic mouse model of pancreatic cancer, where it prolonged survival without significant adverse effects. However, as with any HDAC inhibitor, potential toxicities may include hematological effects (e.g., thrombocytopenia, neutropenia), gastrointestinal disturbances, and cardiotoxicity. Long-term safety studies are needed to fully characterize its toxicity profile. The compound should be handled with standard laboratory precautions and is intended for research use only.
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| References | |
| Additional Infomation |
AES-135 is a hydroxamic acid-based pan-HDAC inhibitor that inhibits HDAC3, HDAC6, HDAC8, and HDAC11 with IC50 values ranging from 190 to 1100 nM. It has been shown to prolong survival in an orthotopic mouse model of pancreatic cancer. AES-135 achieves micromolar blood levels with a Cmax of approximately 10.7 microM and an in vivo half-life of 5 hours. The compound has excellent pharmacokinetic properties in vivo. It is a valuable tool for studying the role of HDACs in cancer and other diseases. AES-135 is available as a research compound and is not approved for clinical use.
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| Molecular Formula |
C33H29F6N3O5S
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| Molecular Weight |
693.655888319016
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| Exact Mass |
693.173
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| CAS # |
2361659-61-0
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| PubChem CID |
137628685
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| Appearance |
White to off-white solid powder
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| LogP |
6.2
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
48
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| Complexity |
1170
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(C1C=CC(=CC=1)F)(N(CC1C(=C(C(=C(C=1F)F)F)F)F)CC(N(C1C=CC(C(NO)=O)=CC=1)CC1C=CC(=CC=1)C(C)(C)C)=O)(=O)=O
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| InChi Key |
LTRKEOBJRDKIHB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C33H29F6N3O5S/c1-33(2,3)21-8-4-19(5-9-21)16-42(23-12-6-20(7-13-23)32(44)40-45)26(43)18-41(48(46,47)24-14-10-22(34)11-15-24)17-25-27(35)29(37)31(39)30(38)28(25)36/h4-15,45H,16-18H2,1-3H3,(H,40,44)
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| Chemical Name |
4-[(4-tert-butylphenyl)methyl-[2-[(4-fluorophenyl)sulfonyl-[(2,3,4,5,6-pentafluorophenyl)methyl]amino]acetyl]amino]-N-hydroxybenzamide
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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 : ~100 mg/mL (~144.16 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.60 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 25.0 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 | 1.4416 mL | 7.2081 mL | 14.4163 mL | |
| 5 mM | 0.2883 mL | 1.4416 mL | 2.8833 mL | |
| 10 mM | 0.1442 mL | 0.7208 mL | 1.4416 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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