Name: PROTAC BRD4 Degrader-1
Brand: BOC Sciences
Rating: 5 (1 reviews)

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Price

Stock

Quantity

$--

In stock

Purity

≥95%

IUPACName

2-[2-[4-[[6-(3,5-dimethyl-1,2-oxazol-4-yl)-1-methyl-2-oxo-4-phenyl-4H-quinazolin-3-yl]methyl]triazol-1-yl]ethoxy]-N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]acetamide

Synonyms

Acetamide, 2-[2-[4-[[6-(3,5-dimethyl-4-isoxazolyl)-1,4-dihydro-1-methyl-2-oxo-4-phenyl-3(2H)-quinazolinyl]methyl]-1H-1,2,3-triazol-1-yl]ethoxy]-N-[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]-; 2-[2-(4-{[6-(3,5-Dimethyl-1,2-oxazol-4-yl)-1-methyl-2-oxo-4-phenyl-1,4-dihydro-3(2H)-quinazolinyl]methyl}-1H-1,2,3-triazol-1-yl)ethoxy]-N-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]acetamide

Melting Point

156-158°C

Density

1.52±0.1 g/cm3

InChI Key

FXNACIMQXOPNJG-UHFFFAOYSA-N

InChI

InChI=1S/C40H37N9O8/c1-22-34(23(2)57-44-22)25-12-13-30-28(18-25)36(24-8-5-4-6-9-24)48(40(55)46(30)3)20-26-19-47(45-43-26)16-17-56-21-33(51)41-29-11-7-10-27-35(29)39(54)49(38(27)53)31-14-15-32(50)42-37(31)52/h4-13,18-19,31,36H,14-17,20-21H2,1-3H3,(H,41,51)(H,42,50,52)

SMILES

CC1=C(C(=NO1)C)C2=CC3=C(C=C2)N(C(=O)N(C3C4=CC=CC=C4)CC5=CN(N=N5)CCOCC(=O)NC6=CC=CC7=C6C(=O)N(C7=O)C8CCC(=O)NC8=O)C

Mechanism

Target: Targets BET bromodomain proteins, especially BRD4, BRD3, and BRD2 for experimental targeted protein degradation studies.

Binding Site: Binds the BET bromodomain acetyl-lysine pocket and recruited E3 ligase ligand site to support productive ternary complex formation.

Mechanism of Action: PROTAC BRD4 Degrader-1 is designed for use in PROTAC or targeted protein degradation experiments directed toward BET bromodomain proteins, especially BRD4, BRD3, and BRD2. 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 BRD4 Degradation: This product is designed to facilitate the targeted degradation of the BRD4 protein, a member of the BET family, which is crucial for transcriptional regulation. Researchers can use this PROTAC to investigate BRD4's role in gene expression and its potential as a therapeutic target in cancer biology.

• Targeted Protein Degradation Studies: PROTAC BRD4 Degrader-1 enables the exploration of selective protein degradation mechanisms within cellular models. By inducing the ubiquitination and subsequent proteasomal degradation of BRD4, this tool aids in elucidating the functional consequences of BRD4 depletion in various biological pathways.

• Epigenetic Regulation Research: Utilizing this PROTAC allows scientists to dissect the involvement of BRD4 in chromatin remodeling and epigenetic modifications. Through targeted degradation, researchers can assess the impact of BRD4 loss on histone acetylation and transcriptional regulation, advancing understanding in epigenetic therapeutics.

• Cancer Research Applications: PROTAC BRD4 Degrader-1 is integral for studying BRD4 as an oncogenic driver. By promoting the degradation of BRD4, researchers can evaluate its contribution to tumorigenesis and identify potential vulnerabilities in cancer cells, facilitating the development of novel anti-cancer strategies.

1. Discovery of a new class of PROTAC BRD4 degraders based on a dihydroquinazolinone derivative and lenalidomide/pomalidomide.

Zhang, F., Wu, Z., Chen, P., Zhang, J., Wang, T., Zhou, J. and Zhang, H., 2020. Bioorganic & Medicinal Chemistry, 28(1), p.115228.

BRD4 has emerged as an attractive target for anticancer therapy. However, BRD4 inhibitors treatment leads to BRD4 protein accumulation, together with the reversible nature of inhibitors binding to BRD4, which may limit the efficacy of BRD4 inhibitors. To address these problems, a protein degradation strategy based on the proteolysis targeting chimera (PROTAC) technology has been developed to target BRD4 recently. Herein, we present our design, synthesis and biological evaluation of a new class of PROTAC BRD4 degraders, which were based on a potent dihydroquinazolinone-based BRD4 inhibitor compound 6 and lenalidomide/pomalidomide as ligand for E3 ligase cereblon. Gratifyingly, several compounds showed excellent inhibitory activity against BRD4, and high anti-proliferative potency against human monocyte lymphoma cell line THP-1. Especially, compound 21 (BRD4 BD1, IC50 = 41.8 nM) achieved a submicromolar IC50 value of 0.81 μM in inhibiting the growth of THP-1 cell line, and was 4 times more potent than compound 6. Moreover, the mechanism study established that 21 could effectively induce the degradation of BRD4 protein and suppression of c-Myc. All of these results suggested that 21 was an efficacious BRD4 degrader for further investigation.

Would you please tell me something about its properties?

Key properties: Potency: PROTAC BRD4 Degrader-1 has an IC50 of 41.8 nM for BRD4 BD1, meaning it requires very low concentrations to effectively degrade the target protein. Selectivity: The molecule specifically targets BRD4 and shows minimal binding to other proteins, reducing the risk of off-target effects. Induces long-lasting degradation: Unlike traditional inhibitors, PROTACs can lead to the permanent removal of target proteins, potentially providing longer-lasting therapeutic effects.

1/3/2018

Good afternoon, I want to know the mechanism of action of this compound.

PROTAC BRD4 Degrader-1 has two key components: A ligand for cereblon: This part of the molecule binds to a protein called cereblon, which acts like a recruiter for the cell's degradation machinery. A ligand for BRD4: This part of the molecule binds to the target protein, BRD4, a protein involved in gene regulation and implicated in various diseases, including cancer. Once bound to both cereblon and BRD4, PROTAC BRD4 Degrader-1 brings them together, forming a ternary complex. Cereblon then tags BRD4 for degradation by the cell's proteasome, effectively removing it from the cell.

11/8/2021

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It is commonly abbreviated as: C₁V₁ = C₂V₂