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PROTAC PD-1/PD-L1 degrader-1 (P22) is a novel First-in-class PD-L1 degrader based on PROTAC technology. With an IC50 of 39.2 nM (HTRF assay), it also prevents the interaction between PD-1/PD-L1. PD-1/PD-L1 interaction is also prevented by it, with an IC50 of 39.2 nM (HTRF assay). P22 also significantly improved the immunity that had been suppressed in a co-culture model using Hep3B/OS-8/hPD-L1 and CD3 T cells. Furthermore, results from flow cytometry (FCM) and western blot analysis revealed that P22 could marginally reduce PD-L1 protein levels in a lysosome-dependent manner, which may aid in the explanation of its immune effects. Preliminary FCM and western-blot data show that it is possible to build PROTAC-like molecules that target PD-L1 from PD-1/PD-L1 small molecule inhibitors, even though these substances only showed modest degradation efficiencies. Overall, the research suggests P22 as a potential starting point for analyzing how PD-L1 can be broken down using a PROTAC-like method.
| Targets |
Cereblon
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|---|---|
| ln Vitro |
PROTAC PD-1/PD-L1 degrader-1 (1–10 M; 24 hours) decreases PD-L1 expression in a dose-dependent manner by 21% and 35% at 1 M and 10 M, respectively[1].
PROTAC PD-1/PD-L1 degrader-1 (1-10 μM; 24 hours) decreases PD-L1 expression in a dose-dependent manner by 21% and 35% at 1 μM and 10 μM, respectively[1]. |
| References |
| Molecular Formula |
C59H58CLN7O11
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|---|---|
| Molecular Weight |
1076.59
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| Exact Mass |
1075.3883
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| Elemental Analysis |
C, 65.82; H, 5.43; Cl, 3.29; N, 9.11; O, 16.35
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| CAS # |
2447066-37-5
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| Related CAS # |
2447066-37-5
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| Appearance |
Solid powder
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| SMILES |
CC1=C(C=CC=C1C2=CC3=C(C=C2)OCCO3)COC4=C(C=C(C(=C4)OCC5=CC(=CC=C5)C#N)CN6CCCCC6C(=O)N7CCN(CC7)C(=O)CCCC(=O)NC8=CC=CC9=C8C(=O)N(C9=O)C1CCC(=O)NC1=O)Cl
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| InChi Key |
CJIXMPCTSMEQPG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C59H58ClN7O11/c1-36-40(10-5-11-42(36)39-17-19-48-51(30-39)76-27-26-75-48)35-78-50-31-49(77-34-38-9-4-8-37(28-38)32-61)41(29-44(50)60)33-66-21-3-2-14-47(66)58(73)65-24-22-64(23-25-65)54(70)16-7-15-52(68)62-45-13-6-12-43-55(45)59(74)67(57(43)72)46-18-20-53(69)63-56(46)71/h4-6,8-13,17,19,28-31,46-47H,2-3,7,14-16,18,20-27,33-35H2,1H3,(H,62,68)(H,63,69,71)
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| Chemical Name |
5-[4-[1-[[5-chloro-2-[(3-cyanophenyl)methoxy]-4-[[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methoxy]phenyl]methyl]piperidine-2-carbonyl]piperazin-1-yl]-N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]-5-oxopentanamide
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| Synonyms |
PD-L1 degrader P22; CUN-01077; CUN 01077; CUN01077
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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: ~210 mg/mL (~195.1 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.4 mg/mL (1.30 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 14.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 1.4 mg/mL (1.30 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 14.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.9289 mL | 4.6443 mL | 9.2886 mL | |
| 5 mM | 0.1858 mL | 0.9289 mL | 1.8577 mL | |
| 10 mM | 0.0929 mL | 0.4644 mL | 0.9289 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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