Name: dBRD9
Brand: BOC Sciences
Rating: 5 (1 reviews)

Purity

≥98%

Solubility

Soluble in DMSO

Appearance

Solid Powder

ShelfLife

2 years

Storage

Store at 2-8°C for short term (days to weeks) or -20°C for long term (months to years)

IUPACName

2-[[2,6-dimethoxy-4-(2-methyl-1-oxo-2,7-naphthyridin-4-yl)phenyl]methyl-methylamino]-N-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethyl]acetamide

Synonyms

dBRD-9; dBRD 9; Acetamide, 2-[[[4-(1,2-dihydro-2-methyl-1-oxo-2,7-naphthyridin-4-yl)-2,6-dimethoxyphenyl]methyl]methylamino]-N-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]ethoxy]ethoxy]ethyl]-; 2-((2,6-dimethoxy-4-(2-methyl-1-oxo-1,2-dihydro-2,7-naphthyridin-4-yl)benzyl)(methyl)amino)-N-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)acetamide

Boiling Point

1014.2±65.0°C at 760 Torr

Density

1.357±0.06 g/cm3

InChI Key

AIOCFZJGGGEWDK-UHFFFAOYSA-N

InChI

InChI=1S/C40H45N7O10/c1-45(21-29-32(54-3)18-24(19-33(29)55-4)28-22-46(2)38(51)27-20-41-11-10-25(27)28)23-35(49)43-13-15-57-17-16-56-14-12-42-30-7-5-6-26-36(30)40(53)47(39(26)52)31-8-9-34(48)44-37(31)50/h5-7,10-11,18-20,22,31,42H,8-9,12-17,21,23H2,1-4H3,(H,43,49)(H,44,48,50)

SMILES

CN1C=C(C2=C(C1=O)C=NC=C2)C3=CC(=C(C(=C3)OC)CN(C)CC(=O)NCCOCCOCCNC4=CC=CC5=C4C(=O)N(C5=O)C6CCC(=O)NC6=O)OC

Mechanism

Target: Targets BRD9 bromodomain protein for experimental targeted protein degradation studies.

Binding Site: Binds the BRD9 acetyl-lysine recognition pocket and cereblon thalidomide-binding domain to support productive ternary complex formation.

Mechanism of Action: dBRD9 is designed for use in PROTAC or targeted protein degradation experiments directed toward BRD9 bromodomain protein. 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 BRD9 Degradation: dBRD9 is designed to facilitate the selective degradation of BRD9, a bromodomain-containing protein implicated in chromatin remodeling. This application allows researchers to study the functional consequences of BRD9 depletion in cellular models, providing insights into its role in transcriptional regulation and potential therapeutic targets.

• Targeted Protein Degradation in Cancer Research: Utilizing dBRD9 enables the investigation of BRD9's involvement in oncogenic pathways. By promoting its degradation, researchers can explore the impact on cancer cell proliferation and survival, offering valuable data for the development of novel anti-cancer strategies that exploit the vulnerabilities of BRD9-dependent tumors.

• Epigenetic Modulation Studies: dBRD9 serves as a powerful tool for probing the epigenetic landscape influenced by BRD9. Through targeted degradation, scientists can dissect the protein's contribution to gene expression regulation, aiding in the understanding of epigenetic mechanisms and their implications in various diseases.

• Chemical Biology and PROTAC Technology Advancement: dBRD9 exemplifies the application of PROTAC technology in chemical biology, providing a model for optimizing degrader design and efficacy. Researchers can use this product to refine strategies for developing next-generation PROTACs with improved specificity and potency for targeted protein degradation applications.

1. Degradation of the BAF complex factor BRD9 by heterobifunctional ligands.

Remillard, D., Buckley, D.L., Paulk, J., Brien, G.L., Sonnett, M., Seo, H.S., Dastjerdi, S., Wühr, M., Dhe-Paganon, S., Armstrong, S.A. and Bradner, J.E., 2017. Angewandte Chemie International Edition, 56(21), pp.5738-5743.

The bromodomain-containing protein BRD9, a subunit of the human BAF (SWI/SNF) nucleosome remodeling complex, has emerged as an attractive therapeutic target in cancer. Despite the development of chemical probes targeting the BRD9 bromodomain, there is a limited understanding of BRD9 function beyond acetyl-lysine recognition. We have therefore created the first BRD9-directed chemical degraders, through iterative design and testing of heterobifunctional ligands that bridge the BRD9 bromodomain and the cereblon E3 ubiquitin ligase complex. Degraders of BRD9 exhibit markedly enhanced potency compared to parental ligands (10- to 100-fold). Parallel study of degraders with divergent BRD9-binding chemotypes in models of acute myeloid leukemia resolves bromodomain polypharmacology in this emerging drug class. Together, these findings reveal the tractability of non-BET bromodomain containing proteins to chemical degradation, and highlight lead compound dBRD9 as a tool for the study of BRD9.

2. Iterative design and optimization of initially inactive proteolysis targeting chimeras (PROTACs) identify VZ185 as a potent, fast, and selective von Hippel-Lindau (VHL) based dual degrader probe of BRD9 and BRD7.

Zoppi, V., Hughes, S.J., Maniaci, C., Testa, A., Gmaschitz, T., Wieshofer, C., Koegl, M., Riching, K.M., Daniels, D.L., Spallarossa, A. and Ciulli, A., 2018. Journal of medicinal chemistry, 62(2), pp.699-726.

Developing PROTACs to redirect the ubiquitination activity of E3 ligases and potently degrade a target protein within cells can be a lengthy and unpredictable process, and it remains unclear whether any combination of E3 and target might be productive for degradation. We describe a probe-quality degrader for a ligase-target pair deemed unsuitable: the von Hippel-Lindau (VHL) and BRD9, a bromodomain-containing subunit of the SWI/SNF chromatin remodeling complex BAF. VHL-based degraders could be optimized from suboptimal compounds in two rounds by systematically varying conjugation patterns and linkers and monitoring cellular degradation activities, kinetic profiles, and ubiquitination, as well as ternary complex formation thermodynamics. The emerged structure-activity relationships guided the discovery of VZ185, a potent, fast, and selective degrader of BRD9 and of its close homolog BRD7. Our findings qualify a new chemical tool for BRD7/9 knockdown and provide a roadmap for PROTAC development against seemingly incompatible target-ligase combinations.

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Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂