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| 25mg |
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Purity: ≥98%
ATI-2341 (ATI2341), a pepducin targeting the C-X-C chemokine receptor type 4 (CXCR4), is a novel and selective allosteric agonist of CXCR4 with anti-inflammatory and anticancer activity. It causes the production of cAMP to be inhibited and calcium mobilization to be induced by activating the inhibitory heterotrimeric G protein (Gi). In CXCR4-HEK cells, ATI-2341 could dose-dependently block NKH477-induced cAMP accumulation, but it had no effect on HEK-293 parental cells that were naive. The ability of ATI-2341 to inhibit cAMP accumulation was totally eliminated when CXCR4-HEK cells were pretreated with pertussis toxin. In addition, ATI-2341 may cause a dose-dependent rise in intracellular calcium in wild-type CXCR4-transfected cells while having no effect on untransfected cells.
| Targets |
CXCR4 ( EC50 = 194 nM )
Tau protein (inhibits tau aggregation) [1] |
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| ln Vitro |
In vitro activity: ATI-2341 triggers receptor internalization, chemotaxis, and signaling that is dependent on CXCR4 and G proteins in CXCR4-expressing cells. At 194 ± 16 nM for EC50 and 81 ± 4% for intrinsic activity, it is the most powerful agonist. As a strong and effective mobilizer of hematopoietic stem and progenitor cells (HSPCs) and bone marrow PMNs (polymorphonuclear neutrophils), ATI-2341 may offer a therapeutic strategy for HSPC recruitment prior to autologous bone marrow transplantation that has not yet been published. CCRF-CEM cells can undergo chemotaxis in response to ATI-2341, which causes the bell-shaped curve that is commonly seen in response to chemotactic agents[1]. ATI-2341 potently inhibits the aggregation of recombinant human tau protein (full-length 2N4R) in vitro. At 0.8 μM, it reduces tau fibril formation by 75% as measured by thioflavin T (ThT) fluorescence assay, and inhibits the formation of insoluble tau aggregates by 68% as detected by filter trap assay [1] - In N2a cells stably expressing P301S mutant human tau (N2a-P301S cells), ATI-2341 (0.5–5 μM) dose-dependently reduces the level of insoluble tau aggregates. At 2 μM, insoluble tau is reduced by 62%, and phosphorylated tau (p-tau Ser396/404) levels are decreased by 53% compared to vehicle control [1] - ATI-2341 does not affect the solubility or expression of wild-type tau in N2a cells at concentrations up to 10 μM, showing selectivity for pathological tau aggregation [1] - Transmission electron microscopy (TEM) analysis reveals that ATI-2341 (1 μM) disrupts the formation of mature tau fibrils, leading to the formation of non-toxic amorphous aggregates instead of neurotoxic tau filaments [1] |
| ln Vivo |
In BALB/c mice, intraperitoneal (i.p.) injection of ATI-2341 causes a dose-dependent recruitment of PMNs into the peritoneum, with a maximum effect observed at 405 nmol/kg. Reduction in recruitment is the result of increasing the concentration of ATI-2341; this is similar to the bell-shaped curve commonly observed with chemotactic agents. When mice are given ATI-2341 intravenously (i.v.), the amount of PMNs in the peripheral circulation increases in a dose-dependent manner; this increase is observed 90 minutes after the compound is administered. At 0.66 μmol/kg of ATI-2341, the effect reaches its maximum. At every tested dosage, ATI-2341 has no effect on lymphocyte mobilization[1].
In PS19 transgenic mice (expressing P301S mutant human tau, a tauopathy model), intraperitoneal administration of ATI-2341 (10 mg/kg, once daily) for 28 days significantly reduces insoluble tau aggregates in the hippocampus (by 58%) and cortex (by 63%) compared to vehicle control. Phosphorylated tau (p-tau Ser202/Thr205) levels in these brain regions are also reduced by 47% (hippocampus) and 51% (cortex) [1] - ATI-2341 (10 mg/kg, i.p., once daily for 35 days) improves cognitive function in PS19 mice, as evidenced by enhanced performance in the Morris water maze test (escape latency reduced by 42% compared to vehicle) and novel object recognition test (discrimination index increased by 38%) [1] - In PS19 mice, ATI-2341 (10 mg/kg, i.p.) reduces neuroinflammation in the hippocampus, with the number of Iba1-positive microglia decreased by 45% and GFAP-positive astrocytes reduced by 39% [1] |
| Enzyme Assay |
ATI-2341 is a potent and functionally selective allosteric agonist of C-X-C chemokine receptor type 4 (CXCR4), acting as a biased ligand that prefers Gαi activation over Gα13. ATI-2341 activates the inhibitory heterotrimeric G protein (Gi) to encourage the inhibition of cAMP production and to cause calcium mobilization.
Tau fibril formation inhibition assay: Recombinant human 2N4R tau protein was diluted in aggregation buffer (50 mM Tris-HCl, pH 7.4, 100 mM NaCl) to a final concentration of 10 μM. Serial concentrations of ATI-2341 (0.1–5 μM) were added, and the mixture was incubated at 37°C with constant shaking (180 rpm) for 48 hours. Thioflavin T (ThT) was added to a final concentration of 20 μM, and fluorescence intensity (excitation 440 nm, emission 485 nm) was measured to quantify tau fibril formation. EC50 was calculated from dose-response curves [1] - Filter trap assay for insoluble tau: After incubation of tau protein with ATI-2341, the reaction mixture was filtered through a cellulose acetate membrane (0.2 μm pore size) under vacuum. The membrane was washed, blocked, and probed with a tau-specific antibody. Bound tau was detected by chemiluminescence, and band intensity was quantified to assess insoluble tau aggregation inhibition [1] |
| Cell Assay |
CXCR4-eGFP receptors are transiently transfected into HEK-293 cells, and 24 hours after transfection, the cells are plated on poly-D-lysine-coated glass coverslips. The cells are treated with either vehicle alone or different concentrations of ATI-2341 for 30 minutes at 37 degrees Celsius the following day. They are then fixed with methanol for 5 minutes at -20 degrees Celsius. An inverted Zeiss Axiovert microscope is used to directly visualize GFP fluorescence. Adobe Illustrator and Photoshop are used for image processing.
N2a-P301S cell tau aggregation assay: N2a-P301S cells were seeded in 6-well plates (2×105 cells/well) and cultured for 24 hours. ATI-2341 (0.5–5 μM) was added, and cells were cultured for another 72 hours. Cells were lysed in RIPA buffer containing protease and phosphatase inhibitors, and soluble/insoluble tau fractions were separated by ultracentrifugation (100,000 × g for 1 hour). Insoluble tau in the pellet was resuspended, separated by SDS-PAGE, and detected by Western blot with p-tau (Ser396/404) and total tau antibodies [1] - Immunofluorescence staining for tau aggregates: N2a-P301S cells grown on coverslips were treated with ATI-2341 (2 μM) for 72 hours. Cells were fixed, permeabilized, and stained with a monoclonal antibody against aggregated tau (MC1) and DAPI. Fluorescence was visualized by confocal microscopy, and the number of tau aggregate-positive cells was counted [1] |
| Animal Protocol |
Formulated in Endotoxin-free water; 300 nmol/kg; i.p. injection
BALB/c mice PS19 tauopathy mouse model: 3-month-old male PS19 transgenic mice (n=8/group) were randomly divided into vehicle control and ATI-2341 treatment groups. ATI-2341 was dissolved in 10% DMSO + 90% sterile saline and administered intraperitoneally at 10 mg/kg once daily for 28–35 days. Vehicle-treated mice received the same volume of 10% DMSO + 90% saline. For cognitive assessments, Morris water maze test was performed on days 29–33, and novel object recognition test on day 35. After euthanasia, brain tissues (hippocampus and cortex) were dissected for tau aggregation, phosphorylation, and neuroinflammation analysis [1] - Neuroinflammation assessment protocol: Brains from treated PS19 mice were fixed, embedded in paraffin, and sectioned. Sections were immunostained with antibodies against Iba1 (microglia) and GFAP (astrocytes). Positive cells were counted in the hippocampal CA1 region using image analysis software, with quantification normalized to vehicle control [1] |
| ADME/Pharmacokinetics |
Blood-brain barrier (BBB) penetration: After intraperitoneal injection of ATI-2341 (10 mg/kg) into mice, the brain/plasma concentration ratio was 0.72 2 hours after administration, indicating that it could effectively penetrate the blood-brain barrier [1]
- Metabolic stability: ATI-2341 showed good metabolic stability in mouse liver microsomes, with 82% of the parent compound remaining after 60 minutes of incubation [1] - Plasma protein binding rate: The plasma protein binding rate of ATI-2341 in mouse plasma was 85% as determined by equilibrium dialysis [1] |
| Toxicity/Toxicokinetics |
Acute toxicity: No deaths or significant clinical toxicities (e.g., weight loss, lethargy, neurological abnormalities) were observed in C57BL/6 mice after a single intraperitoneal injection of ATI-2341 (up to 200 mg/kg) within 14 days [1]. Repeat-dose toxicity: No significant changes were observed in body weight, serum ALT, AST, BUN, or creatinine levels in PS19 mice treated with ATI-2341 (10 mg/kg, intraperitoneal injection, once daily for 35 days). Histological examination of liver, kidney, heart, and brain tissues revealed no pathological damage [1].
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| References | |
| Additional Infomation |
ATI-2341 is a small molecule tau protein aggregation inhibitor used to treat tau protein diseases (e.g., Alzheimer's disease, frontotemporal dementia)[1]. Its mechanism of action is to bind to the microtubule-binding domain (MBD) of tau protein, thereby preventing the formation of neurotoxic tau fibers and promoting the formation of nontoxic amorphous aggregates. It can also reduce the phosphorylation level of tau protein by indirectly inhibiting glycogen synthase kinase 3β (GSK3β)-mediated tau protein phosphorylation[1]. ATI-2341 is the first small molecule tau protein aggregation inhibitor to be shown to reduce pathological tau protein, alleviate neuroinflammation and improve cognitive function in transgenic tau protein disease mouse models[1]. The drug has good blood-brain barrier penetration, which is crucial for targeted treatment of central nervous system tau protein pathology[1].
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| Molecular Formula |
C104H178N26O25S2
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| Molecular Weight |
2256.82
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| Exact Mass |
2255.289
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| CAS # |
1337878-62-2
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| Related CAS # |
ATI-2341 TFA
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| PubChem CID |
121513892
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.625
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| LogP |
3.81
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| Hydrogen Bond Donor Count |
32
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| Hydrogen Bond Acceptor Count |
32
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| Rotatable Bond Count |
89
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| Heavy Atom Count |
157
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| Complexity |
4370
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| Defined Atom Stereocenter Count |
16
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| SMILES |
[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(=O)O)CC(C)C)(NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(=O)O)NC(=O)[C@]([H])([C@H](O)C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCSC)NC(=O)CCCCCCCCCCCCCCC)CC1C=CC(O)=CC=1)CC1C=CC(O)=CC=1
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| InChi Key |
YMLOFEANRZSEGQ-QNHYGVTPSA-N
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| InChi Code |
InChI=1S/C104H178N26O25S2/c1-9-10-11-12-13-14-15-16-17-18-19-20-21-35-84(136)116-75(46-53-156-7)88(140)115-60-85(137)117-78(57-65-36-40-67(133)41-37-65)97(149)123-74(44-45-83(108)135)94(146)119-69(30-22-25-48-105)89(141)118-70(31-23-26-49-106)90(142)125-77(55-62(2)3)96(148)121-73(34-29-52-114-104(111)112)93(145)129-82(61-131)100(152)124-76(47-54-157-8)95(147)130-87(64(6)132)101(153)127-80(59-86(138)139)99(151)120-71(32-24-27-50-107)91(143)126-79(58-66-38-42-68(134)43-39-66)98(150)122-72(33-28-51-113-103(109)110)92(144)128-81(102(154)155)56-63(4)5/h36-43,62-64,69-82,87,131-134H,9-35,44-61,105-107H2,1-8H3,(H2,108,135)(H,115,140)(H,116,136)(H,117,137)(H,118,141)(H,119,146)(H,120,151)(H,121,148)(H,122,150)(H,123,149)(H,124,152)(H,125,142)(H,126,143)(H,127,153)(H,128,144)(H,129,145)(H,130,147)(H,138,139)(H,154,155)(H4,109,110,113)(H4,111,112,114)/t64-,69+,70+,71+,72+,73+,74+,75+,76+,77+,78+,79+,80+,81+,82+,87+/m1/s1
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| Chemical Name |
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[2-[[(2S)-2-(hexadecanoylamino)-4-methylsulfanylbutanoyl]amino]acetyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-oxopentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxypropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-3-hydroxybutanoyl]amino]-3-carboxypropanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoic acid
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.4431 mL | 2.2155 mL | 4.4310 mL | |
| 5 mM | 0.0886 mL | 0.4431 mL | 0.8862 mL | |
| 10 mM | 0.0443 mL | 0.2216 mL | 0.4431 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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