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| Targets |
PD-1/PD-L1[1]
PD-L1 (Programmed death-ligand 1) is a transmembrane protein expressed on the surface of tumor cells and antigen-presenting cells. The interaction between PD-L1 on tumor cells and PD-1 on T cells leads to T cell exhaustion, anergy, and immune evasion. PD-1/PD-L1-IN-23 is an ester prodrug of L7, a benzo[c][1,2,5]oxadiazole derivative that is biologically evaluated as an inhibitor of PD-L1. Upon oral administration, the prodrug is converted to the active L7 moiety, which binds to PD-L1 and blocks its interaction with PD-1, thereby restoring T cell-mediated antitumor immunity. |
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| ln Vitro |
In vitro, PD-1/PD-L1-IN-23 is a potent inhibitor of the PD-1/PD-L1 protein-protein interaction. As a prodrug, it is converted to the active L7 moiety, which exhibits inhibitory activity against PD-L1. The compound enhances T cell activation and cytokine production in functional assays. The prodrug design of PD-1/PD-L1-IN-23 is intended to improve oral bioavailability and pharmacokinetic properties compared to the parent compound L7, which may have limited oral absorption.
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| ln Vivo |
In vivo, PD-1/PD-L1-IN-23 displays significant antitumor effects in tumor models of syngeneic and PD-L1 humanized mice. The compound shows high tumor penetration and favorable pharmacokinetic properties. Oral administration of PD-1/PD-L1-IN-23 results in robust antitumor activity, with tumor growth inhibition and prolonged survival in treated animals. The efficacy of PD-1/PD-L1-IN-23 is comparable to that of other small-molecule PD-L1 inhibitors and supports its further development as an oral immune checkpoint inhibitor.
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| Enzyme Assay |
The in vitro enzyme/receptor binding (cell-free) assay for PD-1/PD-L1-IN-23 typically involves surface plasmon resonance (SPR) or ELISA-based competition assays to measure the affinity of the active L7 metabolite to PD-L1. PD-L1 is immobilized on a sensor chip or microplate, and various concentrations of L7 are incubated to determine the equilibrium dissociation constant (Kd). Competition assays are performed to determine the IC50 for inhibition of PD-1/PD-L1 binding by incubating L7 with PD-L1 and PD-1 proteins and measuring the residual binding using HTRF or ELISA.
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| Cell Assay |
In vitro cellular assays for PD-1/PD-L1-IN-23 use human peripheral blood mononuclear cells (PBMCs) co-cultured with PD-L1-expressing tumor cells. The compound is added at various concentrations, and T cell activation is assessed by measuring the release of IFN-γ and other cytokines using ELISA. T cell proliferation is measured by [³H]-thymidine incorporation or CFSE dilution. The enhancement of tumor cell killing by PBMCs is evaluated using cytotoxicity assays. The prodrug is typically tested alongside the active L7 metabolite to compare their activities.
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| Animal Protocol |
In vivo animal experiments for PD-1/PD-L1-IN-23 are conducted in syngeneic and PD-L1 humanized mouse tumor models. The compound is administered orally at various dose levels. Tumor growth inhibition is assessed by measuring tumor volumes over time. Survival rates are monitored. Immune cell infiltration into tumors is evaluated by immunohistochemistry for CD8+ T cells and other immune markers. Pharmacodynamic endpoints include the measurement of serum cytokine levels and the quantification of immune cell populations in peripheral blood and lymphoid organs.
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| ADME/Pharmacokinetics |
PD-1/PD-L1-IN-23 is an orally active prodrug with favorable pharmacokinetic properties including high tumor penetration. The prodrug design is intended to enhance oral bioavailability compared to the parent compound L7. The compound has a molecular weight of 703.41 g/mol and a molecular formula of C32H30BrCl2N3O6. The ester prodrug is cleaved in vivo to release the active L7 moiety, which exerts the PD-L1 inhibitory activity. The pharmacokinetic profile supports once-daily oral dosing.
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| Toxicity/Toxicokinetics |
Toxicology data for PD-1/PD-L1-IN-23 are limited. The compound has shown significant antitumor effects in mouse models, indicating an acceptable safety profile at efficacious doses. No significant body weight loss or mortality has been reported in treated animals. Further toxicological evaluation is needed to assess the safety of PD-1/PD-L1-IN-23 for potential clinical development. The compound is intended for research purposes only and is not approved for human use.
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| References | |
| Additional Infomation |
PD-1/PD-L1-IN-23 (CAS: 2597056-04-5) is a research compound developed as an orally available small-molecule inhibitor of the PD-1/PD-L1 immune checkpoint pathway. The compound is an ester prodrug of L7, a benzooxadiazole derivative. PD-1/PD-L1-IN-23 is not approved for human use and is intended for research purposes only. The compound represents a promising approach to developing oral PD-1/PD-L1 inhibitors with improved pharmacokinetic properties through prodrug design.
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| Molecular Formula |
C32H30BRCL2N3O6
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|---|---|
| Molecular Weight |
703.41
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| Exact Mass |
701.069
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| CAS # |
2597056-04-5
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| PubChem CID |
164185614
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
14
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| Heavy Atom Count |
44
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| Complexity |
856
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O(C1C=C(OCC2C=CC=C(C3C=CC=CC=3)C=2Br)C(Cl)=CC=1CN[C@H](CO)C(=O)OCC)CC1C=CC2=NON=C2C=1.Cl
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| InChi Key |
RDOKDKCLEBIFLB-LNLSOMNWSA-N
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| InChi Code |
InChI=1S/C32H29BrClN3O6.ClH/c1-2-40-32(39)28(17-38)35-16-23-14-25(34)30(15-29(23)41-18-20-11-12-26-27(13-20)37-43-36-26)42-19-22-9-6-10-24(31(22)33)21-7-4-3-5-8-21;/h3-15,28,35,38H,2,16-19H2,1H3;1H/t28-;/m1./s1
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| Chemical Name |
ethyl (2R)-2-[[2-(2,1,3-benzoxadiazol-5-ylmethoxy)-4-[(2-bromo-3-phenylphenyl)methoxy]-5-chlorophenyl]methylamino]-3-hydroxypropanoate;hydrochloride
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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: 250 mg/mL (355.41 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (2.96 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 20.8 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: ≥ 2.08 mg/mL (2.96 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 20.8 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 | 1.4216 mL | 7.1082 mL | 14.2165 mL | |
| 5 mM | 0.2843 mL | 1.4216 mL | 2.8433 mL | |
| 10 mM | 0.1422 mL | 0.7108 mL | 1.4216 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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