Name: ZXH 3-26
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥98% by HPLC

Solubility

Soluble in DMSO (100 mM), Ethanol (10 mM)

Appearance

Yellow Solid

Storage

Store at -20°C

IUPACName

methyl 2-[(9S)-7-(4-chlorophenyl)-4-[5-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]pentylcarbamoyl]-5,13-dimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate

Synonyms

methyl 2-((6S)-4-(4-chlorophenyl)-2-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)carbamoyl)-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate; Methyl {(6S)-4-(4-chlorophenyl)-2-[(5-{[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]amino}pentyl)carbamoyl]-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl}acetate; 6H-Thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid, 4-(4-chlorophenyl)-2-[[[5-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]pentyl]amino]carbonyl]-3,9-dimethyl-, methyl ester, (6S)-; Methyl (6S)-4-(4-chlorophenyl)-2-[[[5-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]pentyl]amino]carbonyl]-3,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetate; ZXH 3-26

Density

1.55±0.1 g/cm3

InChI Key

OTKOFICOCDRNDA-PMCHYTPCSA-N

InChI

InChI=1S/C38H37ClN8O7S/c1-19-29-31(21-10-12-22(39)13-11-21)42-25(18-28(49)54-3)33-45-44-20(2)46(33)38(29)55-32(19)35(51)41-17-6-4-5-16-40-24-9-7-8-23-30(24)37(53)47(36(23)52)26-14-15-27(48)43-34(26)50/h7-13,25-26,40H,4-6,14-18H2,1-3H3,(H,41,51)(H,43,48,50)/t25-,26?/m0/s1

SMILES

CC1=C(SC2=C1C(=NC(C3=NN=C(N32)C)CC(=O)OC)C4=CC=C(C=C4)Cl)C(=O)NCCCCCNC5=CC=CC6=C5C(=O)N(C6=O)C7CCC(=O)NC7=O

Mechanism

Target: ZXH 3-26 selectively targets BRD4 while sparing BRD2 and BRD3 degradation.

Binding site: Its BRD4 ligand binds bromodomain acetyl-lysine recognition pockets.

Mechanism of action: ZXH 3-26 is a cereblon-recruiting BRD4 PROTAC designed to achieve BRD4-selective degradation within the BET protein family. The molecule links a BRD4-recognition ligand to a CRBN ligand in an arrangement that supports a productive BRD4–PROTAC–CRBN ternary complex. This induced proximity promotes BRD4 ubiquitination and proteasomal depletion with minimal BRD2 or BRD3 degradation under reported conditions. ZXH 3-26 is useful for studying BRD4-specific transcriptional regulation, BET paralog selectivity, ternary-complex geometry, chromatin-associated signaling, and degradation-dependent phenotypes distinct from pan-BET bromodomain inhibition.

Applications

• PROTAC-Mediated Kinase Degradation: ZXH 3-26 is instrumental in the targeted degradation of specific kinases, facilitating the study of kinase-dependent signaling pathways. By selectively degrading these proteins, researchers can dissect the roles they play in cellular processes and uncover potential therapeutic targets.

• Targeted Oncoprotein Degradation: Utilizing ZXH 3-26 allows for the selective degradation of oncoproteins, providing insights into cancer biology. This application aids in understanding the molecular underpinnings of cancer progression and offers a platform for identifying novel anti-cancer strategies.

• PROTAC-Induced Protein Knockdown: ZXH 3-26 serves as a valuable tool for achieving protein knockdown in cellular models. This approach helps elucidate protein function by enabling the temporal control of protein levels, offering a dynamic method for studying cellular responses to protein depletion.

• E3 Ligase Recruitment Studies: By engaging E3 ligases, ZXH 3-26 facilitates the study of ubiquitination processes. This application is crucial for exploring the mechanisms of protein ubiquitination and degradation, contributing to the broader understanding of proteostasis and its implications in disease.

1. Plasticity in binding confers selectivity in ligand-induced protein degradation.

Nowak, R.P., DeAngelo, S.L., Buckley, D., He, Z., Donovan, K.A., An, J., Safaee, N., Jedrychowski, M.P., Ponthier, C.M., Ishoey, M. and Zhang, T., 2018. Nature chemical biology, 14(7), pp.706-714.

Heterobifunctional small-molecule degraders that induce protein degradation through ligase-mediated ubiquitination have shown considerable promise as a new pharmacological modality. However, we currently lack a detailed understanding of the molecular basis for target recruitment and selectivity, which is critically required to enable rational design of degraders. Here we utilize a comprehensive characterization of the ligand-dependent CRBN-BRD4 interaction to demonstrate that binding between proteins that have not evolved to interact is plastic. Multiple X-ray crystal structures show that plasticity results in several distinct low-energy binding conformations that are selectively bound by ligands. We demonstrate that computational protein-protein docking can reveal the underlying interprotein contacts and inform the design of a BRD4 selective degrader that can discriminate between highly homologous BET bromodomains. Our findings that plastic interprotein contacts confer selectivity for ligand-induced protein dimerization provide a conceptual framework for the development of heterobifunctional ligands.

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