Name: MZ2
Brand: BOC Sciences
Rating: 5 (1 reviews)

Size

Price

Stock

Quantity

$--

In stock

ShelfLife

2 years

IUPACName

(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.0^2,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]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

MZ 2; MZ-2; (2S,4R)-1-((S)-2-(tert-butyl)-20-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-4,19-dioxo-6,9,12,15-tetraoxa-3,18-diazaicosanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; N-{17-[(6S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-16-oxo-3,6,9,12-tetraoxa-15-azaheptadecan-1-oyl}-3-methyl-L-valyl-(4R)-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)benzyl]-L-prolinamide; L-Prolinamide, N-[17-[(6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl]-1,16-dioxo-3,6,9,12-tetraoxa-15-azaheptadec-1-yl]-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-, (4R)-

Density

1.38±0.1 g/cm3

InChI Key

LSELSHXLKGXPPF-BOBBFQORSA-N

InChI

InChI=1S/C51H64ClN9O9S2/c1-30-32(3)72-50-43(30)44(35-12-14-37(52)15-13-35)56-39(47-59-58-33(4)61(47)50)25-41(63)53-16-17-67-18-19-68-20-21-69-22-23-70-28-42(64)57-46(51(5,6)7)49(66)60-27-38(62)24-40(60)48(65)54-26-34-8-10-36(11-9-34)45-31(2)55-29-71-45/h8-15,29,38-40,46,62H,16-28H2,1-7H3,(H,53,63)(H,54,65)(H,57,64)/t38-,39+,40+,46-/m1/s1

SMILES

CC1=C(SC2=C1C(=NC(C3=NN=C(N32)C)CC(=O)NCCOCCOCCOCCOCC(=O)NC(C(=O)N4CC(CC4C(=O)NCC5=CC=C(C=C5)C6=C(N=CS6)C)O)C(C)(C)C)C7=CC=C(C=C7)Cl)C

Mechanism

Target: MZ2 targets BRD4, a bromodomain and extra-terminal chromatin reader protein.

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

Mechanism of action: MZ2 is a VHL-recruiting BRD4 PROTAC related to the MZ series of BET degraders. The compound is designed to connect a BRD4-recognition ligand with a von Hippel-Lindau ligand, enabling induced proximity between BRD4 and VHL-containing E3 ubiquitin ligase machinery. This ternary-complex mechanism supports BRD4 ubiquitination and proteasome-dependent degradation, allowing researchers to examine BRD4 protein loss rather than bromodomain inhibition alone. MZ2 is useful for studying BET degrader structure-activity relationships, ternary-complex formation, BRD4-selective chromatin regulation, and degradation-dependent transcriptional phenotypes.

Applications

• PROTAC-Mediated Kinase Degradation: MZ2 is specifically designed to facilitate the targeted degradation of kinases, offering a powerful tool for dissecting kinase signaling pathways. By leveraging the ubiquitin-proteasome system, researchers can study the functional consequences of kinase removal in cellular contexts, advancing our understanding of kinase-related diseases.

• Targeted Degradation of Oncoproteins: MZ2 enables the selective degradation of oncoproteins, providing a strategic approach to investigate oncogenic signaling. This application aids in elucidating the roles of specific oncoproteins in cancer progression, offering insights into potential therapeutic targets for novel anti-cancer strategies.

• PROTAC-Based Neurodegeneration Research: Utilizing MZ2, researchers can explore the degradation of proteins implicated in neurodegenerative disorders. By targeting misfolded or aggregated proteins, this approach helps in understanding disease mechanisms and identifying potential pathways for intervention in conditions such as Alzheimer's or Parkinson's disease.

• Degradation of Immune Checkpoints: MZ2 serves as a valuable tool in immunology research by enabling the degradation of immune checkpoint proteins. This application supports studies on immune regulation and the development of innovative strategies to enhance immune responses against various diseases, including cancer.

1. Impact of target warhead and linkage vector on inducing protein degradation: comparison of bromodomain and extra-terminal (BET) degraders derived from triazolodiazepine (JQ1) and tetrahydroquinoline (I-BET726) BET inhibitor scaffolds.

Chan, K.H., Zengerle, M., Testa, A. and Ciulli, A., 2018. Journal of medicinal chemistry, 61(2), pp.504-513.

The design of proteolysis-targeting chimeras (PROTACs) is a powerful small-molecule approach for inducing protein degradation. PROTACs conjugate a target warhead to an E3 ubiquitin ligase ligand via a linker. Here we examined the impact of derivatizing two different BET bromodomain inhibitors, triazolodiazepine JQ1 and the more potent tetrahydroquinoline I-BET726, via distinct exit vectors, using different polyethylene glycol linkers to VHL ligand VH032. Triazolodiazepine PROTACs exhibited positive cooperativities of ternary complex formation and were more potent degraders than tetrahydroquinoline compounds, which showed negative cooperativities instead. Marked dependency on linker length was observed for BET-degrading and cMyc-driven antiproliferative activities in acute myeloid leukemia cell lines. This work exemplifies as a cautionary tale how a more potent inhibitor does not necessarily generate more potent PROTACs and underscores the key roles played by the conjugation. The provided insights and framework for structure-activity relationships of bivalent degraders are anticipated to have wide future applicability.

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