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.
Physicochemical Properties
| Molecular Formula | C59H58CLN7O11 |
| Molecular Weight | 1076.59 |
| Exact Mass | 1075.388 |
| Elemental Analysis | C, 65.82; H, 5.43; Cl, 3.29; N, 9.11; O, 16.35 |
| CAS # | 2447066-37-5 |
| Related CAS # | 2447066-37-5 |
| PubChem CID | 146673162 |
| Appearance | White to off-white solid powder |
| LogP | 6.3 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 13 |
| Rotatable Bond Count | 16 |
| Heavy Atom Count | 78 |
| Complexity | 2220 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | 0 |
| InChi Key | CJIXMPCTSMEQPG-UHFFFAOYSA-N |
| 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) |
| 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 |
| Synonyms | PD-L1 degrader P22; CUN-01077; CUN 01077; CUN01077 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| Targets | Cereblon |
| 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 |
[1]. Discovery of novel resorcinol diphenyl ether-based PROTAC-like molecules as dual inhibitors and degraders of PD-L1. Eur J Med Chem. 2020;199:112377. |
Solubility Data
| Solubility (In Vitro) | DMSO: ~210 mg/mL (~195.1 mM) |
| 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 |