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ADH-503 [(Z)-Leukadherin-1 choline] is a novel, potent, selective, orally bioactive and allosteric agonist of the integrin CD11b to mitigate myeloid cell immunosuppression. The partial activation of CD11b by ADH-503 leads to the repolarization of tumor-associated macrophages, reduction in the number of tumor-infiltrating immunosuppressive myeloid cells, and enhanced dendritic cell responses. These actions, in turn, improve antitumor T cell immunity and render checkpoint inhibitors effective in previously unresponsive PDAC models.
| ln Vitro |
The number of CD11b+ monocytes, granulocytes, eosinophils, and macrophage subsets as well as the total number of tumor-infiltrating CD11b+ cells are decreased by ADH-503 ((Z)-Leukadherin-1 choline; 4 μM; 8 days) [1].
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| ln Vivo |
Reducing tumor burden increases overall survival. ADH-503 ((Z)-Leukadherin-1 choline; oral gavage; 30, 60, or 120 mg/kg; twice daily for 60 days) delayed tumor progression, leading to substantial differences in time-point analyses and therapy [1]. ADH-503 (oral gavage; 30, 100 mg/kg; twice daily; days 1 and 5) has an AUC0-t 30 at the mg/kg and 100 mg/kg doses, with plasma concentrations of 6950 ng.h/mL and 13962 ng.h/mL, respectively. Its highest concentration is 1716 and 2594 ng/mL. The mean half-life is 4.68 and 3.95 hours.
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| Animal Protocol |
Animal/Disease Models: KPC mouse [p48-CRE/Lox-stop-Lox(LSL)-KrasG12D/p53flox/flox][1]
Doses: 30, 60 or 120 mg/kg Route of Administration: po (oral gavage); 60-day Experimental Results: Delays tumor progression, results in Dramatically lower tumor burden in time point analysis, and improves overall survival. Animal/Disease Models: Male rat[1] Doses: 30, 100 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: po (oral gavage), twice (two times) daily; results on days 1 and 5: 30 mg and 100 mg, the average half-lives were 4.68 and 3.95 hrs (hrs (hours)), respectively, the maximum concentrations were 1716 and 2594 ng/mL, and the AUC0-t in plasma were 6950 and 13962 ng.h/mL/kg respectively. |
| References |
[1]. Panni RZ, et al. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med. 2019 Jul 3;11(499).
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| Molecular Formula |
C28H32N2O4S2
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|---|---|
| Molecular Weight |
524.651624679565
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| CAS # |
2055362-74-6
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| Related CAS # |
Leukadherin-1;344897-95-6;(Z)-Leukadherin-1;2055362-72-4
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| SMILES |
C[N+](C)(C)CCO.O=C([O-])C1=CC=C(C2=CC=C(/C=C(SC(N3CC4=CC=CC=C4)=S)/C3=O)O2)C=C1
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| InChi Key |
GOWDQYRMBCOOJR-JHMJKTBASA-M
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| InChi Code |
InChI=1S/C22H15NO4S2.C5H14NO/c24-20-19(29-22(28)23(20)13-14-4-2-1-3-5-14)12-17-10-11-18(27-17)15-6-8-16(9-7-15)21(25)261-6(2,3)4-5-7/h1-12H,13H2,(H,25,26)7H,4-5H2,1-3H3/q+1/p-1/b19-12-
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| Chemical Name |
2-hydroxy-N,N,N-trimethylethan-1-aminium (Z)-4-(5-((3-benzyl-4-oxo-2-thioxothiazolidin-5-ylidene)methyl)furan-2-yl)benzoate
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| Synonyms |
ADH-503 choline ADH-503 ADH 503 ADH503 Leukadherin-1 choline LA1
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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) |
MEthanol : ~100 mg/mL (~190.60 mM)
DMSO : ~21.43 mg/mL (~40.85 mM) Ethanol : ~3.33 mg/mL (~6.35 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.14 mg/mL (4.08 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 21.4 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.14 mg/mL (4.08 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 21.4 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 2.08 mg/mL (3.96 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9060 mL | 9.5302 mL | 19.0603 mL | |
| 5 mM | 0.3812 mL | 1.9060 mL | 3.8121 mL | |
| 10 mM | 0.1906 mL | 0.9530 mL | 1.9060 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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