Name: PROTAC BRD4 Degrader-2
Brand: BOC Sciences
Rating: 5 (1 reviews)

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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-oxo-3H-isoindol-4-yl]acetamide

Synonyms

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-oxo-2,3-dihydro-1H-isoindol-4-yl]acetamide; 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-oxo-1H-isoindol-4-yl]-

Melting Point

172-174°C

Density

1.48±0.1 g/cm3

InChI Key

LSXNGBATZZFCNR-UHFFFAOYSA-N

InChI

InChI=1S/C40H39N9O7/c1-23-36(24(2)56-44-23)26-12-13-32-29(18-26)37(25-8-5-4-6-9-25)49(40(54)46(32)3)20-27-19-47(45-43-27)16-17-55-22-35(51)41-31-11-7-10-28-30(31)21-48(39(28)53)33-14-15-34(50)42-38(33)52/h4-13,18-19,33,37H,14-17,20-22H2,1-3H3,(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=C6CN(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-2 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: PROTAC BRD4 Degrader-2 is engineered to selectively induce the degradation of BRD4, a pivotal protein in epigenetic regulation. This application facilitates the study of BRD4's role in transcriptional control and its implications in oncogenic processes, offering insights into novel cancer therapy strategies.

• Targeted Protein Degradation in Cancer Research: Utilizing PROTAC BRD4 Degrader-2 enables researchers to explore targeted degradation pathways, providing a robust tool to dissect the mechanistic underpinnings of BRD4 in tumorigenesis. This aids in the identification of potential therapeutic targets and the development of innovative treatment modalities.

• Epigenetic Modulation Studies: By employing PROTAC BRD4 Degrader-2, scientists can effectively modulate epigenetic landscapes through targeted protein degradation. This application is critical for investigating chromatin dynamics and transcriptional regulation, advancing our understanding of epigenetic contributions to disease states.

• Drug Discovery and Development: PROTAC BRD4 Degrader-2 serves as a valuable asset in drug discovery pipelines, offering a unique approach to validate BRD4 as a therapeutic target. This facilitates the design of next-generation therapeutics aimed at precise protein degradation, enhancing the specificity and efficacy of drug candidates.

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.

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It is commonly abbreviated as: C₁V₁ = C₂V₂