| Size | Price | Stock | Qty |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| Other Sizes |
| Targets |
Sirtuin 2 (SIRT2) (inhibitor) [1]
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| ln Vitro |
On Drosophila with Huntington's disease, AK-1 at 10 μM had a strong neuroprotective effect, increasing the number of striated muscles from 5.2 to 5.6 [1]. With an IC50 of 12.5 μM, AK-1 is a powerful, selective, and cell-permeable inhibitor of SIRT2 [2]. By blocking the NF-κB/CSN2 pathway, AK-1 therapy causes the Snail transcription factor to be broken down by proteases. Decreased snail levels cause p21 to be overexpressed, which slows down wound healing, G1 arrest, and proliferation. In HT-29 colon cancer cells, AK-1 also regulates the Snail-p21 axis [3]. In hypoxic environments, AK-1 enhances HIF-1α's ubiquitination in a VHL-dependent manner, which triggers HIF-1α's destruction via the proteasomal route. Downregulating HIF-1α expression in AK-1-treated cells lowers its transcriptional activity, which in turn lowers the expression of BNIP3, one of the HIF-1 target genes [4].
In primary striatal neurons expressing a mutant huntingtin fragment (Htt171-82Q), treatment with AK-1 (1, 2, and 4 μM) dose-dependently rescued neuronal viability, as measured by NeuN-positive cell counts. [1] AK-1 treatment (2 μM, 7 days) significantly reduced the number of mutant huntingtin inclusions in Htt171-82Q-expressing primary striatal neurons. [1] Microarray analysis of primary striatal neurons treated with AK-1 (2 μM, 48 hours) revealed significant downregulation of genes involved in sterol biosynthesis, including multiple enzymes in the cholesterol synthesis pathway. This effect was confirmed by qPCR. [1] AK-1 treatment (5 μM, 48 hours) significantly reduced sterol (cholesterol and cholesteryl esters) levels in primary striatal neurons expressing Htt171-82Q, as well as in untransduced and Htt171-18Q-expressing neurons. [1] AK-1 (20 μM, 1 hour) reduced the nuclear trafficking of the sterol regulatory element-binding protein 2 (SREBP-2) in primary striatal neurons, as visualized by immunocytochemistry. [1] The neuroprotective effect of AK-1 was abrogated by overexpression of wild-type SIRT2, confirming on-target activity. [1] |
| ln Vivo |
In a Drosophila melanogaster model of Huntington's disease (expressing Httex1 Q93 in all neurons), feeding flies with medium supplemented with AK-1 (10 μM) for 7 days significantly improved photoreceptor neuron survival, as assessed by the pseudopupil technique. The number of surviving rhabdomeres per ommatidium increased from 5.2 to 5.5 (P < 0.02). [1]
In a Caenorhabditis elegans model of Huntington's disease (expressing polyQ N-ter Htt in touch receptor neurons), treatment with AK-1 (100 μM) for 48 hours significantly rescued the defective touch response. The improvement was specific to mutant polyQ-expressing animals. [1] |
| Cell Assay |
Primary Striatal Neuron Culture and Viability: Primary striatal neurons from embryonic rats were transduced with lentiviral vectors expressing Htt171-18Q or Htt171-82Q. Neurons were treated with varying concentrations of AK-1 (1, 2, 4 μM) starting on day 3 after transduction. At 14 days post-transduction, cells were fixed and stained with an antibody against NeuN (a neuronal marker). The number of NeuN-positive cells was counted in multiple fields per condition to assess neuronal survival. [1]
Inclusion Body Analysis: Primary striatal neurons expressing Htt171-82Q were treated with AK-1 (2 μM). Cells were immunostained with an antibody against huntingtin (EM48) to visualize inclusions. The number of cells with inclusions was quantified. [1] Gene Expression Analysis (Microarray and qPCR): Primary striatal neurons (untransduced or expressing Htt171-18Q/82Q) were treated with AK-1 (2 μM) for 48 hours. Total RNA was extracted and processed for microarray hybridization. Data were analyzed to identify differentially expressed genes and pathways. Select gene changes were confirmed by quantitative real-time PCR. [1] Sterol Measurement: Primary striatal neurons were treated with AK-1 (5 μM) for 48 hours. Cellular lipids were extracted, and levels of cholesterol and cholesteryl esters were quantified using an enzymatic assay. [1] SREBP-2 Nuclear Trafficking Assay: Primary striatal neurons were treated with AK-1 (20 μM) for 1 hour. Cells were fixed and immunostained for endogenous SREBP-2 and counterstained with DAPI. The percentage of cells with predominantly nuclear SREBP-2 localization was determined by microscopy. [1] |
| Animal Protocol |
Drosophila* Model:** Freshly eclosed flies expressing Httex1 Q93 pan-neuronally were fed standard medium supplemented with AK-1 (10 μM) or vehicle for 7 days. Neurodegeneration was assessed using the pseudopupil technique, which counts the number of surviving rhabdomeres (photoreceptor neurons) per ommatidium. [1]
* ***C. elegans* Model:** Worms expressing polyQ N-ter Htt in touch receptor neurons were placed on agar plates containing AK-1 (100 μM) or vehicle for 48 hours. The touch response was evaluated by gently stroking the tail with a hair and recording the animal's response. [1] Drosophila Model: Freshly eclosed flies expressing Httex1 Q93 pan-neuronally were fed standard medium supplemented with AK-1 (10 μM) or vehicle for 7 days. Neurodegeneration was assessed using the pseudopupil technique, which counts the number of surviving rhabdomeres (photoreceptor neurons) per ommatidium. [1] C. elegans Model: Worms expressing polyQ N-ter Htt in touch receptor neurons were placed on agar plates containing AK-1 (100 μM) or vehicle for 48 hours. The touch response was evaluated by gently stroking the tail with a hair and recording the animal's response. [1] |
| References |
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| Additional Infomation |
AK-1 is a selective, structurally diverse small-molecule inhibitor of sirtuin 2 (SIRT2). It was previously identified and characterized as part of a effort to find neuroprotective compounds for Parkinson's disease. [1]
This study demonstrates that AK-1 is neuroprotective in multiple models of Huntington's disease, including Drosophila, C. elegans, and primary mammalian neurons. [1] The mechanism of neuroprotection for AK-1 is linked to the downregulation of sterol biosynthesis. By inhibiting SIRT2, AK-1 reduces the nuclear trafficking of the transcription factor SREBP-2, leading to decreased expression of cholesterol synthesis genes and lower cellular sterol levels. This counteracts the sterol dyshomeostasis induced by mutant huntingtin. [1] AK-1's neuroprotective effect is confirmed to be on-target, as it is blocked by overexpression of wild-type SIRT2 and mimicked by a dominant-negative SIRT2 mutant. [1] |
| Exact Mass |
403.12
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|---|---|
| CAS # |
330461-64-8
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| PubChem CID |
1341463
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.630
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| LogP |
4.11
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
28
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| Complexity |
650
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(C1=C([H])C([H])=C([H])C(C(N([H])C2C([H])=C([H])C([H])=C(C=2[H])[N+](=O)[O-])=O)=C1[H])(N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H])(=O)=O
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| InChi Key |
HAYBKCHPEBZNGW-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H21N3O5S/c23-19(20-16-8-6-9-17(14-16)22(24)25)15-7-5-10-18(13-15)28(26,27)21-11-3-1-2-4-12-21/h5-10,13-14H,1-4,11-12H2,(H,20,23)
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| Chemical Name |
3-(azepan-1-ylsulfonyl)-N-(3-nitrophenyl)benzamide
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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 : ≥ 50 mg/mL (~123.93 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.20 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.) |
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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03210740 | COMPLETED | Drug: AM001 Cream, 7.5% Drug: Vehicle Cream |
Actinic Keratosis | AmDerma | 2017-06-06 | Phase 2 |
| NCT06092346 | RECRUITING | AK1, OMIM *103000, Adenylate Kinase Deficiency ADA2, OMIM *607575,Sneddon Syndrome; VAIHS ADSL, OMIM *608222, Adenylosuccinate Lyase Deficiency AICDA, OMIM *605257, Immunodeficiency With Hyper-IgM, Type 2; HIGM2 |
2023-12-19 | |||
| NCT05865730 | RECRUITING | Other: Live Bacterial Product - Akkermansia muciniphila | Carcinoma, Non-Small-Cell Lung Carcinoma, Renal Cell |
EverImmune | 2022-10-01 | Phase 2 |
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