| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
| Targets |
Glucocorticoid receptor agonist-3 Ala-Ala-Mal targets two distinct entities: the glucocorticoid receptor (GR) via its agonist payload and TNFα via the anti-human TNFα antibody component. The glucocorticoid receptor is a nuclear receptor that, upon activation by glucocorticoids, translocates to the nucleus and modulates the transcription of anti-inflammatory genes while repressing pro-inflammatory gene expression. TNFα is a pro-inflammatory cytokine that plays a central role in the pathogenesis of autoimmune and inflammatory diseases.
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| ln Vitro |
As an antibody-drug conjugate, the in vitro activity of Glucocorticoid receptor agonist-3 Ala-Ala-Mal is characterized by its ability to bind to TNFα-expressing cells and deliver the glucocorticoid agonist payload. The conjugate is expected to retain the glucocorticoid receptor agonist activity of the payload component, which includes potent anti-inflammatory effects through modulation of gene expression. The antibody component provides specificity for TNFα, potentially reducing systemic exposure and off-target effects compared to unconjugated glucocorticoids.
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| ln Vivo |
In vivo activity of Glucocorticoid receptor agonist-3 Ala-Ala-Mal is being investigated in preclinical models of autoimmune and inflammatory diseases. The antibody-glucocorticoid conjugate format is designed to deliver the glucocorticoid agonist specifically to sites of TNFα expression, thereby concentrating the anti-inflammatory effect at diseased tissues while minimizing systemic glucocorticoid exposure. This targeted approach has the potential to improve the therapeutic index of glucocorticoids, which are limited by significant systemic side effects when used chronically.
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| Enzyme Assay |
Non-cell-based binding assays for Glucocorticoid receptor agonist-3 Ala-Ala-Mal typically involve measuring the affinity of the antibody component for TNFα and the binding of the glucocorticoid agonist payload to the glucocorticoid receptor. A standard protocol for TNFα binding includes ELISA or surface plasmon resonance (SPR) using immobilized TNFα protein and varying concentrations of the conjugate. Glucocorticoid receptor binding affinity can be assessed using radioligand binding assays with purified GR protein or cell lysates expressing GR. The Ala-Ala-Mal linker stability can also be evaluated in plasma or serum to assess the rate of payload release.
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| Cell Assay |
Cellular assays for Glucocorticoid receptor agonist-3 Ala-Ala-Mal typically involve TNFα-expressing cell lines or primary immune cells. A representative protocol includes culturing cells (e.g., THP-1 monocytes or primary macrophages) in appropriate medium, treating with the conjugate at various concentrations (0.001–100 μg/mL) for 24–72 hours, and measuring downstream effects. TNFα neutralization can be assessed by measuring cytokine production (e.g., IL-6, IL-8) by ELISA. Glucocorticoid receptor activation can be confirmed by measuring the expression of glucocorticoid-responsive genes (e.g., GILZ, MKP-1) by qRT-PCR.
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| Animal Protocol |
In vivo animal studies with Glucocorticoid receptor agonist-3 Ala-Ala-Mal are conducted in murine models of autoimmune and inflammatory diseases, such as collagen-induced arthritis, experimental autoimmune encephalomyelitis, or DSS-induced colitis. A typical protocol involves administering the conjugate via intravenous or intraperitoneal injection at doses ranging from 1 to 30 mg/kg, with treatment regimens varying from single dose to repeated dosing over several weeks. Disease severity is monitored through clinical scoring, histopathological analysis of target tissues, and measurement of inflammatory markers in serum or tissue homogenates.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Glucocorticoid receptor agonist-3 Ala-Ala-Mal are characteristic of antibody-drug conjugates, with a long half-life determined primarily by the antibody component. The conjugate is expected to exhibit limited distribution to peripheral tissues, with prolonged circulation and gradual accumulation at sites of TNFα expression. The Ala-Ala-Mal linker is designed for controlled release of the glucocorticoid agonist payload, which may occur through enzymatic cleavage in the target tissue or through pH-dependent mechanisms. The compound is stored as a powder at -20°C for up to 3 years.
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| Toxicity/Toxicokinetics |
As a research compound, Glucocorticoid receptor agonist-3 Ala-Ala-Mal is not intended for human therapeutic use, and comprehensive toxicological data are limited to preclinical studies. Standard safety assessments would include cytotoxicity screening, immunogenicity testing of the antibody component, and preliminary toxicology studies in animal models to evaluate maximum tolerated dose and identify potential target organs of toxicity. The compound should be stored at -20°C in a sealed container, protected from moisture and light.
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| References | |
| Additional Infomation |
Glucocorticoid receptor agonist-3 Ala-Ala-Mal (Compound Preparation 8) is referenced in patent WO2023220549A1, which describes anti-human TNFα antibody-glucocorticoid conjugates for the treatment of autoimmune and inflammatory diseases. The Ala-Ala-Mal designation indicates the specific linker-payload configuration used in this conjugate, which is designed to enable controlled release of the glucocorticoid agonist. This targeted approach represents an innovative strategy for improving the therapeutic index of glucocorticoids, which are widely used but limited by significant systemic side effects when administered systemically.
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| Exact Mass |
910.38
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|---|---|
| CAS # |
3014393-35-9
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| PubChem CID |
169494531
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| Appearance |
White to off-white solid powder
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| Density |
1.42±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)
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| Boiling Point |
1119.2±65.0 °C(predicted)
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| LogP |
0
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
14
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| Heavy Atom Count |
66
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| Complexity |
2060
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| Defined Atom Stereocenter Count |
11
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| SMILES |
CC1=C(C(=C(C=C1)OCC2=CC(=CC=C2)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)CCN3C(=O)C=CC3=O)F)[C@H]4O[C@@H]5C[C@H]6[C@@H]7CCC8=CC(=O)C=C[C@@]8([C@H]7[C@H](C[C@@]6([C@@]5(O4)C(=O)CO)C)O)C
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| InChi Key |
BISHTACTVXELTJ-VFAPTOKSSA-N
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| InChi Code |
InChI=1S/C49H55FN4O12/c1-25-9-12-35(64-24-28-7-6-8-30(19-28)53-45(63)27(3)52-44(62)26(2)51-38(59)16-18-54-39(60)13-14-40(54)61)43(50)41(25)46-65-37-21-33-32-11-10-29-20-31(56)15-17-47(29,4)42(32)34(57)22-48(33,5)49(37,66-46)36(58)23-55/h6-9,12-15,17,19-20,26-27,32-34,37,42,46,55,57H,10-11,16,18,21-24H2,1-5H3,(H,51,59)(H,52,62)(H,53,63)/t26-,27-,32-,33-,34-,37+,42+,46-,47-,48-,49+/m0/s1
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| Chemical Name |
(2S)-2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]-N-[(2S)-1-[3-[[2-fluoro-3-[(1S,2S,4R,6S,8S,9S,11S,12S,13R)-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-16-oxo-5,7-dioxapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-6-yl]-4-methylphenoxy]methyl]anilino]-1-oxopropan-2-yl]propanamide
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 (~109.77 mM; with sonication)
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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.) |
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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