Name: dTRIM 24
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

Purity

≥98%

Solubility

Soluble in DMSO, Ethanol

Appearance

White Solid

ShelfLife

2 years

Storage

Store at -20°C

IUPACName

(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[[3-[[1,3-dimethyl-2-oxo-6-(3-propoxyphenoxy)benzimidazol-5-yl]sulfamoyl]benzoyl]amino]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

Synonyms

(2S,4R)-1-((S)-15-(tert-Butyl)-1-(3-(N-(1,3-dimethyl-2-oxo-6-(3-propoxyphenoxy)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)sulfamoyl)phenyl)-1,13-dioxo-5,8,11-trioxa-2,14-diazahexadecan-16-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; dTRIM24; dTRIM-24

Density

1.316±0.06 g/cm3

InChI Key

QUQTXFIMYFMULC-OGOZKGDESA-N

InChI

InChI=1S/C55H68N8O13S2/c1-8-20-75-40-12-10-13-41(28-40)76-47-30-45-44(61(6)54(69)62(45)7)29-43(47)60-78(70,71)42-14-9-11-38(26-42)51(66)56-19-21-72-22-23-73-24-25-74-33-48(65)59-50(55(3,4)5)53(68)63-32-39(64)27-46(63)52(67)57-31-36-15-17-37(18-16-36)49-35(2)58-34-77-49/h9-18,26,28-30,34,39,46,50,60,64H,8,19-25,27,31-33H2,1-7H3,(H,56,66)(H,57,67)(H,59,65)/t39-,46+,50-/m1/s1

SMILES

CCCOC1=CC=CC(=C1)OC2=C(C=C3C(=C2)N(C(=O)N3C)C)NS(=O)(=O)C4=CC=CC(=C4)C(=O)NCCOCCOCCOCC(=O)NC(C(=O)N5CC(CC5C(=O)NCC6=CC=C(C=C6)C7=C(N=CS7)C)O)C(C)(C)C

Mechanism

Target: dTRIM24 selectively targets tripartite motif-containing protein 24, an epigenetic reader protein.

Binding site: Its TRIM24 ligand binds the PHD-bromodomain histone-recognition module.

Mechanism of action: dTRIM24 is a VHL-recruiting PROTAC chemical probe designed to degrade TRIM24 selectively. It combines a TRIM24 reader-domain ligand with a von Hippel-Lindau E3 ligase ligand, enabling formation of a ternary complex that recruits TRIM24 to ubiquitination machinery. Subsequent proteasomal degradation removes the full TRIM24 protein, allowing evaluation of functions beyond bromodomain occupancy alone. In research workflows, dTRIM24 supports studies of chromatin regulation, transcriptional control, apoptosis-associated phenotypes, and comparisons between pharmacological inhibition of TRIM24 domains and complete degradation of the multidomain epigenetic regulator.

Applications

• PROTAC-Mediated Degradation: dTRIM 24 is designed to facilitate the targeted degradation of the TRIM24 protein, a key regulator in various cellular processes. By harnessing the ubiquitin-proteasome system, dTRIM 24 selectively degrades TRIM24, offering researchers a powerful tool to study its role in oncogenesis and transcriptional regulation.

• Targeted Protein Degradation in Cancer Research: Utilizing dTRIM 24 enables the exploration of TRIM24's involvement in tumor progression. By selectively degrading TRIM24, researchers can dissect its contribution to cancer cell survival and proliferation, providing insights into potential therapeutic strategies for targeting TRIM24-associated pathways.

• Functional Genomics Studies: dTRIM 24 serves as a valuable asset in functional genomics, allowing scientists to investigate the downstream effects of TRIM24 depletion. This can help elucidate the protein's role in gene expression regulation and identify novel targets for drug development in diseases where TRIM24 is implicated.

• Mechanistic Studies of Ubiquitin-Proteasome Pathway: dTRIM 24 provides a model to study the mechanistic aspects of the ubiquitin-proteasome pathway in targeted protein degradation. Researchers can gain insights into the efficiency and specificity of PROTAC-induced degradation, advancing the understanding of this technology in protein homeostasis.

1. Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands.

Gechijian, L.N., Buckley, D.L., Lawlor, M.A., Reyes, J.M., Paulk, J., Ott, C.J., Winter, G.E., Erb, M.A., Scott, T.G., Xu, M. and Seo, H.S., 2018. Nature chemical biology, 14(4), pp.405-412.

The addressable pocket of a protein is often not functionally relevant in disease. This is true for the multidomain, bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders. Recruitment of the VHL E3 ubiquitin ligase by dTRIM24 elicits potent and selective degradation of TRIM24. Using dTRIM24 to probe TRIM24 function, we characterize the dynamic genome-wide consequences of TRIM24 loss on chromatin localization and gene control. Further, we identify TRIM24 as a novel dependency in acute leukemia. Pairwise study of TRIM24 degradation versus bromodomain inhibition reveals enhanced anti-proliferative response from degradation. We offer dTRIM24 as a chemical probe of an emerging cancer dependency, and establish a path forward for numerous selective yet ineffectual ligands for proteins of therapeutic interest.

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