Name: PROTAC EED degrader-2
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥98%

Solubility

Soluble in DMSO

Storage

Store at -20°C, protect from light, stored under nitrogen

IUPACName

(2S,4R)-1-[(2S)-2-[5-[3-[5-[5-[(5-fluoro-2,3-dihydro-1-benzofuran-4-yl)methylamino]-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl]-6-methylpyridin-2-yl]propanoylamino]pentanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Synonyms

N-[5-({3-[5-(5-{[(5-Fluoro-2,3-dihydro-1-benzofuran-4-yl)methyl]amino}[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methyl-2-pyridinyl]propanoyl}amino)pentanoyl]-3-methyl-L-valyl-(4R)-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)benzyl]-L-prolinamide; L-Prolinamide, N-[5-[[3-[5-[5-[[(5-fluoro-2,3-dihydro-4-benzofuranyl)methyl]amino]-1,2,4-triazolo[4,3-c]pyrimidin-8-yl]-6-methyl-2-pyridinyl]-1-oxopropyl]amino]-1-oxopentyl]-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-, (4R)-

Density

1.40±0.1 g/cm3

InChI Key

CQSOTYMFUWTIIR-HUSBZTEESA-N

InChI

InChI=1S/C50H58FN11O6S/c1-29-35(38-25-55-49(62-27-57-60-46(38)62)54-24-37-36-19-21-68-41(36)17-16-39(37)51)15-13-33(58-29)14-18-42(64)52-20-7-6-8-43(65)59-45(50(3,4)5)48(67)61-26-34(63)22-40(61)47(66)53-23-31-9-11-32(12-10-31)44-30(2)56-28-69-44/h9-13,15-17,25,27-28,34,40,45,63H,6-8,14,18-24,26H2,1-5H3,(H,52,64)(H,53,66)(H,54,55)(H,59,65)/t34-,40+,45-/m1/s1

SMILES

CC1=C(C=CC(=N1)CCC(=O)NCCCCC(=O)NC(C(=O)N2CC(CC2C(=O)NCC3=CC=C(C=C3)C4=C(N=CS4)C)O)C(C)(C)C)C5=CN=C(N6C5=NN=C6)NCC7=C(C=CC8=C7CCO8)F

Mechanism

Target: Targets EED subunit of the PRC2 chromatin-repressive complex for experimental targeted protein degradation studies.

Binding Site: Binds the EED aromatic cage ligand pocket and recruited E3 ligase site to support productive ternary complex formation.

Mechanism of Action: PROTAC EED degrader-2 is designed for use in PROTAC or targeted protein degradation experiments directed toward EED subunit of the PRC2 chromatin-repressive complex. 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

• EED PROTAC Degradation: PROTAC EED degrader-2 facilitates the selective degradation of the embryonic ectoderm development (EED) protein, a core component of the polycomb repressive complex 2 (PRC2). This enables researchers to explore the functional consequences of EED loss in epigenetic regulation and chromatin remodeling processes.

• Epigenetic Modulation Studies: By targeting EED for degradation, this PROTAC allows for the investigation of epigenetic modifications and their role in gene expression regulation. It provides a valuable tool for dissecting the mechanisms of PRC2-mediated transcriptional repression in various biological contexts.

• Mechanistic Insights into PRC2: Utilizing PROTAC EED degrader-2, researchers can gain mechanistic insights into PRC2 complex dynamics and its involvement in developmental and disease-related pathways. This aids in understanding how targeted protein degradation can influence cellular processes and phenotypic outcomes.

• Drug Discovery and Development: As a tool for targeted protein degradation, PROTAC EED degrader-2 supports drug discovery efforts by validating EED as a therapeutic target. It assists in identifying potential small molecules that can modulate PRC2 activity through induced protein degradation.

1. EED-targeted PROTACs degrade EED, EZH2, and SUZ12 in the PRC2 complex.

Hsu, J.H.R., Rasmusson, T., Robinson, J., Pachl, F., Read, J., Kawatkar, S., O'Donovan, D.H., Bagal, S., Code, E., Rawlins, P. and Argyrou, A., 2020. Cell chemical biology, 27(1), pp.41-46.

Deregulation of the PRC2 complex, comprised of the core subunits EZH2, SUZ12, and EED, drives aberrant hypermethylation of H3K27 and tumorigenicity of many cancers. Although inhibitors of EZH2 have shown promising clinical activity, preclinical data suggest that resistance can be acquired through secondary mutations in EZH2 that abrogate drug target engagement. To address these limitations, we have designed several hetero-bifunctional PROTACs (proteolysis-targeting chimera) to efficiently target EED for elimination. Our PROTACs bind to EED (pKD ~ 9.0) and promote ternary complex formation with the E3 ubiquitin ligase. The PROTACs potently inhibit PRC2 enzyme activity (pIC50 ~ 8.1) and induce rapid degradation of not only EED but also EZH2 and SUZ12 within the PRC2 complex. Furthermore, the PROTACs selectively inhibit proliferation of PRC2-dependent cancer cells (half maximal growth inhibition [GI50] = 49-58 nM). In summary, our data demonstrate a therapeutic modality to target PRC2-dependent cancer through a PROTAC-mediated degradation mechanism.

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