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

Size

Price

Stock

Quantity

$--

In stock

Purity

≥95%

Solubility

Soluble in DMSO

Appearance

Off-white Solid

Storage

Store at 2-8°C for short term (days to weeks) or -20°C for long term (months to years)

Shipping

Room temperature in continental US; may vary elsewhere

IUPACName

1-N'-[3-fluoro-4-[7-[2-[2-[2-[2-[[[(2S,4R)-4-hydroxy-1-[(2S)-3-methyl-2-(3-oxo-1H-isoindol-2-yl)butanoyl]pyrrolidine-2-carbonyl]amino]methyl]-5-(4-methyl-1,3-thiazol-5-yl)phenoxy]ethoxy]ethoxy]ethoxy]-6-methoxyquinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Synonyms

SJF-6683; N-{3-Fluoro-4-[(7-{2-[2-(2-{2-[({(4R)-4-hydroxy-1-[(2S)-3-methyl-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)butanoyl]-L-prolyl}amino)methyl]-5-(4-methyl-1,3-thiazol-5-yl)phenoxy}ethoxy)ethoxy]ethoxy}-6-methoxy-4-quinolinyl)oxy]phenyl}-N'-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide; 1,1-Cyclopropanedicarboxamide, N-[4-[[7-[2-[2-[2-[2-[[[[(2S,4R)-1-[(2S)-2-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)-3-methyl-1-oxobutyl]-4-hydroxy-2-pyrrolidinyl]carbonyl]amino]methyl]-5-(4-methyl-5-thiazolyl)phenoxy]ethoxy]ethoxy]ethoxy]-6-methoxy-4-quinolinyl]oxy]-3-fluorophenyl]-N'-(4-fluorophenyl)-

Density

1.389±0.06 g/cm3 (Predicted)

InChI Key

LYUUIIZKBMBNQV-CHOFKVETSA-N

InChI

InChI=1S/C62H63F2N7O12S/c1-36(2)55(71-33-40-7-5-6-8-45(40)58(71)74)59(75)70-34-44(72)29-49(70)57(73)66-32-39-10-9-38(56-37(3)67-35-84-56)27-52(39)81-25-23-79-21-22-80-24-26-82-54-31-48-46(30-53(54)78-4)50(17-20-65-48)83-51-16-15-43(28-47(51)64)69-61(77)62(18-19-62)60(76)68-42-13-11-41(63)12-14-42/h5-17,20,27-28,30-31,35-36,44,49,55,72H,18-19,21-26,29,32-34H2,1-4H3,(H,66,73)(H,68,76)(H,69,77)/t44-,49+,55+/m1/s1

SMILES

CC1=C(SC=N1)C2=CC(=C(C=C2)CNC(=O)C3CC(CN3C(=O)C(C(C)C)N4CC5=CC=CC=C5C4=O)O)OCCOCCOCCOC6=CC7=NC=CC(=C7C=C6OC)OC8=C(C=C(C=C8)NC(=O)C9(CC9)C(=O)NC1=CC=C(C=C1)F)F

Mechanism

Target: SJFδ selectively targets p38δ MAP kinase without degrading p38α, p38β, or p38γ.

Binding site: Its foretinib-derived kinase ligand binds the ATP pocket of p38δ.

Mechanism of action: SJFδ is a VHL-recruiting PROTAC optimized for selective degradation of p38δ MAP kinase. The molecule combines a foretinib-derived kinase-binding element with a von Hippel-Lindau ligand through a defined linker, enabling ternary-complex formation between p38δ and the VHL E3 ligase complex. This induced proximity drives ubiquitination and proteasome-mediated depletion with minimal degradation of other p38 isoforms. SJFδ is valuable for dissecting p38δ-specific signaling functions, separating isoform-selective degradation from broad kinase inhibition, and studying MAPK pathway biology in cellular systems.

Applications

• PROTAC-Mediated Kinase Degradation: SJFδ is utilized in research to selectively degrade kinases implicated in disease pathways. By employing the PROTAC mechanism, SJFδ facilitates the ubiquitination and subsequent proteasomal degradation of target kinases, providing a powerful tool for dissecting kinase function and validating therapeutic targets in cellular models.

• Targeted Protein Degradation in Cancer Research: SJFδ aids in the exploration of oncogenic protein degradation. Researchers leverage its ability to induce the degradation of proteins overexpressed in cancer cells, offering insights into tumor biology and potential avenues for novel cancer therapies through targeted protein degradation strategies.

• Investigating Protein-Protein Interactions: Utilizing SJFδ allows scientists to study the effects of degrading specific proteins involved in critical protein-protein interactions. This application helps elucidate the role of these interactions in cellular processes and diseases, advancing our understanding of complex biological networks.

• Advancing Drug Discovery: SJFδ serves as a pivotal tool in drug discovery research, enabling the identification of novel drug targets through the degradation of proteins previously considered "undruggable." By facilitating targeted protein degradation, SJFδ expands the scope of potential therapeutic interventions.

1. Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase.

Smith, B.E., Wang, S.L., Jaime-Figueroa, S., Harbin, A., Wang, J., Hamman, B.D. and Crews, C.M., 2019. Nature communications, 10(1), pp.1-13.

PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation. Many potent PROTACs with specificity for dissimilar targets have been developed; however, the factors governing degradation selectivity within closely-related protein families remain elusive. Here, we generate isoform-selective PROTACs for the p38 MAPK family using a single warhead (foretinib) and recruited E3 ligase (von Hippel-Lindau). Based on their distinct linker attachments and lengths, these two PROTACs differentially recruit VHL, resulting in degradation of p38α or p38δ. We characterize the role of ternary complex formation in driving selectivity, showing that it is necessary, but insufficient, for PROTAC-induced substrate ubiquitination. Lastly, we explore the p38δ:PROTAC:VHL complex to explain the different selectivity profiles of these PROTACs. Our work attributes the selective degradation of two closely-related proteins using the same warhead and E3 ligase to heretofore underappreciated aspects of the ternary complex model.

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