Name: Pmd-PEG3-BI
Brand: BOC Sciences
Rating: 5 (1 reviews)

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$--

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Purity

≥95%

IUPACName

N-[3-[5-[[1-[3-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]propanoyl]piperidin-4-yl]-methylamino]-3-pyrimidin-5-ylpyrrolo[3,2-b]pyridin-1-yl]-2,4-difluorophenyl]propane-1-sulfonamide

Synonyms

1-Propanesulfonamide, N-[3-[5-[[1-[3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]-1-oxopropyl]-4-piperidinyl]methylamino]-3-(5-pyrimidinyl)-1H-pyrrolo[3,2-b]pyridin-1-yl]-2,4-difluorophenyl]-; N-(3-(5-((1-(3-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoyl)piperidin-4-yl)(methyl)amino)-3-(pyrimidin-5-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-2,4-difluorophenyl)propane-1-sulfonamide; N-[3-[5-[[1-[3-[2-[2-[2-[[2-(2,6-Dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]-1-oxopropyl]-4-piperidinyl]methylamino]-3-(5-pyrimidinyl)-1H-pyrrolo[3,2-b]pyridin-1-yl]-2,4-difluorophenyl]-1-propanesulfonamide; PROTAC BRAF-V600E degrader-1

Density

1.48±0.1 g/cm3

InChI Key

FMUGAZVOOIUFAT-UHFFFAOYSA-N

InChI

InChI=1S/C48H54F2N10O10S/c1-3-25-71(66,67)56-36-8-7-34(49)45(43(36)50)59-28-33(30-26-51-29-52-27-30)44-37(59)9-11-39(54-44)57(2)31-13-17-58(18-14-31)41(62)15-19-68-21-23-70-24-22-69-20-16-53-35-6-4-5-32-42(35)48(65)60(47(32)64)38-10-12-40(61)55-46(38)63/h4-9,11,26-29,31,38,53,56H,3,10,12-25H2,1-2H3,(H,55,61,63)

SMILES

CCCS(=O)(=O)NC1=CC=C(F)C(N2C=C(C3=CN=CN=C3)C3=NC(N(C)C4CCN(C(=O)CCOCCOCCOCCNC5=CC=CC6=C5C(=O)N(C5CCC(=O)NC5=O)C6=O)CC4)=CC=C32)=C1F

Mechanism

Target: Pmd-PEG3-BI targets BRAF, particularly degradation studies involving oncogenic BRAF V600E.

Binding site: Its BRAF inhibitor moiety binds the ATP-competitive kinase pocket of BRAF.

Mechanism of action: Pmd-PEG3-BI is a cereblon-recruiting BRAF PROTAC scaffold containing a BRAF-binding inhibitor, PEG3 linker, and pomalidomide-derived CRBN ligand. The molecule is designed to recruit BRAF to CRL4CRBN ubiquitin ligase machinery, promoting ubiquitination and proteasome-dependent degradation rather than simple RAF kinase inhibition. This approach is useful for studying degradation of BRAF V600E, RAF signaling suppression, dimerization-associated resistance biology, and the extent to which physical removal of BRAF differs from occupancy-driven pathway inhibition in MAPK-dependent cellular models.

Applications

• Protac-Enhanced Drug Discovery: Pmd-PEG3-BI is instrumental in the identification and validation of novel drug targets through PROTAC-mediated targeted protein degradation. By facilitating the selective degradation of disease-relevant proteins, it aids researchers in understanding protein function and interactions, paving the way for innovative therapeutic strategies.

• Targeted Protein Degradation Research: This product provides a powerful tool for studying the mechanisms of targeted protein degradation. Pmd-PEG3-BI allows for the precise elimination of specific proteins, enabling detailed investigations into cellular pathways and the development of more effective degradation-based interventions.

• Protein Function Analysis: Utilizing Pmd-PEG3-BI in experimental setups allows scientists to dissect the roles of specific proteins within complex biological systems. The targeted degradation capability aids in elucidating protein functions, offering insights into cellular processes and potential points of therapeutic intervention.

• Cellular Pathway Exploration: By employing Pmd-PEG3-BI, researchers can systematically degrade key proteins involved in cellular signaling pathways. This approach provides a unique opportunity to map out intricate signaling networks and identify critical nodes that could be targeted for therapeutic benefit using PROTAC technology.

1. Discovery of selective small molecule degraders of BRAF-V600E.

Han, X.R., Chen, L., Wei, Y., Yu, W., Chen, Y., Zhang, C., Jiao, B., Shi, T., Sun, L., Zhang, C. and Xu, Y., 2020. Journal of Medicinal Chemistry, 63(8), pp.4069-4080.

BRAF is among the most frequently mutated oncogenes in human cancers. Multiple small molecule BRAF kinase inhibitors have been approved for treating melanoma carrying BRAF-V600 mutations. However, the benefits of BRAF kinase inhibitors are generally short-lived. Small molecule-mediated targeted protein degradation has recently emerged as a novel pharmaceutical strategy to remove disease proteins through hijacking the cellular ubiquitin proteasome system (UPS). In this study, we developed thalidomide-based heterobifunctional compounds that induced selective degradation of BRAF-V600E, but not the wild-type BRAF. Downregulation of BRAF-V600E suppressed the MEK/ERK kinase cascade in melanoma cells and impaired cell growth in culture. Abolishing the interaction between degraders and cereblon or blocking the UPS significantly impaired the activities of these degraders, validating a mechanistic role of UPS in mediating targeted degradation of BRAF-V600E. These findings highlight a new approach to modulate the functions of oncogenic BRAF mutants and provide a framework to treat BRAF-dependent human cancers.

2. Functional characterization of a PROTAC directed against BRAF mutant V600E.

Posternak, G., Tang, X., Maisonneuve, P., Jin, T., Lavoie, H., Daou, S., Orlicky, S., Goullet de Rugy, T., Caldwell, L., Chan, K. and Aman, A., 2020. Nature chemical biology, 16(11), pp.1170-1178.

The RAF family kinases function in the RAS-ERK pathway to transmit signals from activated RAS to the downstream kinases MEK and ERK. This pathway regulates cell proliferation, differentiation and survival, enabling mutations in RAS and RAF to act as potent drivers of human cancers. Drugs targeting the prevalent oncogenic mutant BRAF(V600E) have shown great efficacy in the clinic, but long-term effectiveness is limited by resistance mechanisms that often exploit the dimerization-dependent process by which RAF kinases are activated. Here, we investigated a proteolysis-targeting chimera (PROTAC) approach to BRAF inhibition. The most effective PROTAC, termed P4B, displayed superior specificity and inhibitory properties relative to non-PROTAC controls in BRAF(V600E) cell lines. In addition, P4B displayed utility in cell lines harboring alternative BRAF mutations that impart resistance to conventional BRAF inhibitors. This work provides a proof of concept for a substitute to conventional chemical inhibition to therapeutically constrain oncogenic BRAF.

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Concentration (start) x Volume (start) = Concentration (final) x Volume (final)
It is commonly abbreviated as: C₁V₁ = C₂V₂