Name: PROTAC PD-1/PD-L1 degrader-1
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

98%

Solubility

Soluble in DMSO

Storage

Store at -20°C

IUPACName

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

5-(4-(1-(5-Chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)piperidine-2-carbonyl)piperazin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)-5-oxopentanamide

Density

1.45±0.1 g/cm3

InChI Key

CJIXMPCTSMEQPG-UHFFFAOYSA-N

InChI

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)

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

Mechanism

Target: Targets PD-L1 within the PD-1/PD-L1 immune checkpoint axis for experimental targeted protein degradation studies.

Binding Site: Binds the PD-L1 extracellular PD-1 interaction interface and CRBN ligand module to support productive ternary complex formation.

Mechanism of Action: PROTAC PD-1/PD-L1 degrader-1 is designed for use in PROTAC or targeted protein degradation experiments directed toward PD-L1 within the PD-1/PD-L1 immune checkpoint axis. The bifunctional molecule links a target-recognition element to cereblon, promoting proximity between the protein of interest and ubiquitination machinery. Productive ternary-complex formation can drive polyubiquitination and proteasome-dependent target depletion, allowing researchers to compare pharmacological inhibition with protein removal. It is suitable for evaluating degradation potency, kinetics, pathway selectivity, and downstream signaling consequences in engineered or disease-relevant cellular models.

Applications

• PROTAC-Mediated Immune Checkpoint Modulation: This product facilitates the targeted degradation of PD-1 and PD-L1 proteins, crucial for studying immune checkpoint pathways. By selectively degrading these proteins, researchers can explore novel approaches to modulate immune responses, providing insights into immune evasion mechanisms in cancer.

• Targeted Protein Degradation in Cancer Research: Utilizing PROTAC PD-1/PD-L1 degrader-1 allows for the precise elimination of PD-1 and PD-L1, offering a powerful tool for investigating their roles in tumor microenvironments. This application aids in understanding how disrupting these pathways can enhance anti-tumor immunity.

• PROTAC-Driven Pathway Analysis: This degrader enables the specific removal of PD-1/PD-L1, facilitating the study of downstream signaling pathways. Researchers can dissect the molecular consequences of protein degradation, providing valuable data on the regulatory networks influenced by these immune checkpoints.

• Selective Protein Degradation for Therapeutic Exploration: By employing this PROTAC, scientists can assess the therapeutic potential of degrading PD-1/PD-L1 in various disease models. This approach supports the development of innovative strategies for immune modulation and cancer therapy research.

1. Discovery of novel resorcinol diphenyl ether-based PROTAC-like molecules as dual inhibitors and degraders of PD-L1.

Cheng, B., Ren, Y., Cao, H. and Chen, J., 2020. European Journal of Medicinal Chemistry, 199, p.112377.

Novel resorcinol diphenyl ether-based PROTACs (PROteolysis TArgeting Chimeras) were designed and evaluated for their inhibitory activity against the programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway and their ability to degrade PD-L1 protein. Most of the compounds displayed excellent inhibitory activities against PD-1/PD-L1, as assessed by the homogenous time-resolved fluorescence (HTRF) binding assay, with IC50 values ranging from 25 nM to 200 nM. Among them, compound P22 is one of the best with an IC50 value of 39.2 nM. In addition to inhibiting PD-1/PD-L1 interaction, P22 also significantly restored the immunity repressed in a co-culture model of Hep3B/OS-8/hPD-L1 and CD3 T cells. Furthermore, flow cytometry (FCM) and western-blot data demonstrated that P22 could moderately reduce the protein levels of PD-L1 in a lysosome-dependent manner, which may contribute to its immune effects. Preliminary FCM and western-blot data suggest that it is possible to build PD-L1-targeting PROTAC-like molecules based on PD-1/PD-L1 small molecule inhibitors, though these compounds showed only modest degradation efficiencies. Collectively, this work suggests that P22 may serve as a starting point for exploring the degradation of PD-L1 by PROTAC-like strategy.

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It is commonly abbreviated as: C₁V₁ = C₂V₂