Name: β-NF-JQ1
Brand: BOC Sciences
Rating: 5 (1 reviews)

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$--

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Purity

≥95%

IUPACName

2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-[2-[2-[2-[[4-(1-oxobenzo[f]chromen-3-yl)phenyl]methoxy]ethoxy]ethoxy]ethyl]acetamide

Synonyms

beta-NF-JQ1; (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(2-(2-((4-(1-oxo-1H-benzo[f]chromen-3-yl)benzyl)oxy)ethoxy)ethoxy)ethyl)acetamide; 6H-Thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide, 4-(4-chlorophenyl)-2,3,9-trimethyl-N-[2-[2-[2-[[4-(1-oxo-1H-naphtho[2,1-b]pyran-3-yl)phenyl]methoxy]ethoxy]ethoxy]ethyl]-, (6S)-; (6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-N-[2-[2-[2-[[4-(1-oxo-1H-naphtho[2,1-b]pyran-3-yl)phenyl]methoxy]ethoxy]ethoxy]ethyl]-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide

Density

1.36±0.1 g/cm3

InChI Key

OZFKLXDOAZGVSV-BHVANESWSA-N

InChI

InChI=1S/C45H42ClN5O6S/c1-27-28(2)58-45-41(27)43(33-12-15-34(46)16-13-33)48-36(44-50-49-29(3)51(44)45)24-40(53)47-18-19-54-20-21-55-22-23-56-26-30-8-10-32(11-9-30)39-25-37(52)42-35-7-5-4-6-31(35)14-17-38(42)57-39/h4-17,25,36H,18-24,26H2,1-3H3,(H,47,53)/t36-/m0/s1

SMILES

O=C1C=C(OC=2C=CC=3C=CC=CC3C12)C=4C=CC(=CC4)COCCOCCOCCNC(=O)CC5N=C(C=6C=CC(Cl)=CC6)C7=C(SC(=C7C)C)N8C(=NN=C85)C

Mechanism

Target: β-NF-JQ1 targets bromodomain-containing proteins through a JQ1-derived BET recognition element.

Binding site: Its JQ1 moiety binds bromodomain acetyl-lysine recognition pockets.

Mechanism of action: β-NF-JQ1 is a noncanonical PROTAC designed to recruit the aryl hydrocarbon receptor-associated degradation machinery to bromodomain-containing proteins. The molecule uses β-naphthoflavone as an AhR ligand and JQ1 as the BRD-targeting ligand, inducing proximity between AhR-associated E3 ligase components and BRD proteins. This interaction promotes protein knockdown and enables evaluation of AhR-based E3 recruitment as an alternative to conventional CRBN or VHL platforms. β-NF-JQ1 is useful for studying bromodomain protein depletion, E3-ligase diversification, and degradation-associated transcriptional responses.

Applications

• PROTAC-Mediated BET Degradation: β-NF-JQ1 is designed to selectively degrade BET proteins, such as BRD4, through the ubiquitin-proteasome system. This application is crucial for studying the role of BET proteins in transcriptional regulation and their potential as therapeutic targets in oncology research.

• Targeted Protein Degradation in Cancer: By facilitating the targeted degradation of oncogenic proteins, β-NF-JQ1 serves as a powerful tool in cancer biology research. It provides insights into the mechanisms of tumorigenesis and aids in the identification of novel cancer treatment strategies through the elimination of specific protein drivers.

• Mechanistic Studies of Protein Function: Utilizing β-NF-JQ1 allows researchers to investigate the functional consequences of BET protein degradation in cellular processes. This application is particularly valuable for elucidating the role of these proteins in gene expression and chromatin remodeling, advancing our understanding of cellular biology.

• Drug Discovery and Development: β-NF-JQ1 is instrumental in the early stages of drug discovery, offering a platform to explore the therapeutic potential of PROTACs. By targeting BET proteins for degradation, it assists in the development of new compounds with improved specificity and efficacy for various diseases.

1. Development of Small Molecule Chimeras That Recruit AhR E3 Ligase to Target Proteins

Nobumichi Ohoka, Takuji Shoda, Yosuke Demizu, Mikihiko Naito, Genichiro Tsuji, Takuma Fujisato, Masaaki Kurihara ACS Chem Biol . 2019 Dec 20;14(12):2822-2832. doi: 10.1021/acschembio.9b00704.

Targeted protein degradation using chimeric small molecules such as proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) is an emerging modality in drug discovery. Here, we expand the repertoire of E3 ligases capable of ubiquitylating target proteins using this system. By incorporating β-naphthoflavone (β-NF) as a ligand, we developed a novel class of chimeric molecules that recruit the arylhydrocarbon receptor (AhR) E3 ligase complex. β-NF-ATRA, a chimeric degrader directed against cellular retinoic acid binding proteins (CRABPs), induced the AhR-dependent degradation of CRABP-1 and CRABP-2 via the ubiquitin-proteasome pathway. A similar compound ITE-ATRA, in which an alternative AhR ligand was used, also degraded CRABP proteins. Finally, we developed a chimeric compound β-NF-JQ1 that is directed against bromodomain-containing (BRD) proteins using β-NF as an AhR ligand. β-NF-JQ1 induced the interaction of AhR and BRD proteins and displayed effective anticancer activity that correlated with protein knockdown activity. These results demonstrate a novel class of chimeric degrader molecules based on the ability to bring a target protein and an AhR E3 ligase into close proximity.

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