Name: SJF-8240
Brand: BOC Sciences
Rating: 5 (1 reviews)

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)

IUPACName

1-N'-[3-fluoro-4-[7-[3-[3-[3-[[(2S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl]amino]-3-oxopropoxy]propoxy]propoxy]-6-methoxyquinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Synonyms

N-[3-(3-{3-[(4-{2-Fluoro-4-[({1-[(4-fluorophenyl)carbamoyl]cyclopropyl}carbonyl)amino]phenoxy}-6-methoxy-7-quinolinyl)oxy]propoxy}propoxy)propanoyl]-3-methyl-L-valyl-(4R)-4-hydroxy-N-[4-(4-methyl-1,3-thiazol-5-yl)benzyl]-L-prolinamide; L-Prolinamide, N-[3-[3-[3-[[4-[2-fluoro-4-[[[1-[[(4-fluorophenyl)amino]carbonyl]cyclopropyl]carbonyl]amino]phenoxy]-6-methoxy-7-quinolinyl]oxy]propoxy]propoxy]-1-oxopropyl]-3-methyl-L-valyl-4-hydroxy-N-[[4-(4-methyl-5-thiazolyl)phenyl]methyl]-, (4R)-

Boiling Point

1226.5±65.0°C at 760 mmHg

Density

1.341±0.1 g/cm3

InChI Key

SCUZPTNDZHEHLB-ZWUDBOSPSA-N

InChI

InChI=1S/C58H65F2N7O11S/c1-35-51(79-34-63-35)37-10-8-36(9-11-37)32-62-53(70)45-29-41(68)33-67(45)54(71)52(57(2,3)4)66-50(69)19-27-76-24-6-23-75-25-7-26-77-49-31-44-42(30-48(49)74-5)46(18-22-61-44)78-47-17-16-40(28-43(47)60)65-56(73)58(20-21-58)55(72)64-39-14-12-38(59)13-15-39/h8-18,22,28,30-31,34,41,45,52,68H,6-7,19-21,23-27,29,32-33H2,1-5H3,(H,62,70)(H,64,72)(H,65,73)(H,66,69)/t41-,45+,52-/m1/s1

SMILES

CC1=C(SC=N1)C2=CC=C(C=C2)CNC(=O)C3CC(CN3C(=O)C(C(C)(C)C)NC(=O)CCOCCCOCCCOC4=CC5=NC=CC(=C5C=C4OC)OC6=C(C=C(C=C6)NC(=O)C7(CC7)C(=O)NC8=CC=C(C=C8)F)F)O

Mechanism

Target: SJF-8240 targets c-MET receptor tyrosine kinase, including exon-14-deleted c-MET.

Binding site: Its foretinib-derived ligand binds the ATP pocket of c-MET kinase domain.

Mechanism of action: SJF-8240, also known as PROTAC 7, is a VHL-recruiting c-MET degrader that links the multikinase inhibitor foretinib to a von Hippel-Lindau ligand. The molecule induces c-MET polyubiquitination and proteasome-dependent degradation, including degradation of exon-14-deleted c-MET in reported cellular models. This mechanism supports analysis of MET-driven signaling through target removal rather than reversible kinase occupancy. SJF-8240 is useful for studying receptor tyrosine kinase degradation, agonist-driven AKT pathway suppression, c-MET dependency, and proliferation responses in MET-amplified or MET-altered experimental systems.

Applications

• PROTAC-Mediated Protein Degradation: SJF-8240 is utilized to selectively degrade target proteins through the ubiquitin-proteasome system. By linking an E3 ligase ligand to a specific protein binder, it facilitates the ubiquitination and subsequent degradation of proteins, offering a powerful tool for studying protein function and regulation.

• Targeted Degradation of Oncoproteins: Researchers employ SJF-8240 to specifically degrade cancer-associated oncoproteins. This targeted approach allows for the investigation of oncogenic pathways and the identification of novel therapeutic targets, providing insights into cancer biology and potential intervention strategies.

• Investigating Protein-Protein Interactions: SJF-8240 aids in probing complex protein-protein interactions by removing specific proteins from cellular pathways. This targeted degradation approach helps elucidate the roles of individual proteins within signaling networks, enhancing our understanding of cellular processes and disease mechanisms.

• Modulating Cellular Pathways: By degrading key regulatory proteins, SJF-8240 serves as a valuable tool for modulating cellular pathways. This application is crucial for dissecting the intricacies of cell signaling and identifying critical nodes for therapeutic intervention in various diseases.

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.

2. Lessons in PROTAC design from selective degradation with a promiscuous warhead.

Bondeson, D.P., Smith, B.E., Burslem, G.M., Buhimschi, A.D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B.D., Ishchenko, A. and Crews, C.M., 2018. Cell chemical biology, 25(1), pp.78-87.

Inhibiting protein function selectively is a major goal of modern drug discovery. Here, we report a previously understudied benefit of small molecule proteolysis-targeting chimeras (PROTACs) that recruit E3 ubiquitin ligases to target proteins for their ubiquitination and subsequent proteasome-mediated degradation. Using promiscuous CRBN- and VHL-recruiting PROTACs that bind >50 kinases, we show that only a subset of bound targets is degraded. The basis of this selectivity relies on protein-protein interactions between the E3 ubiquitin ligase and the target protein, as illustrated by engaged proteins that are not degraded as a result of unstable ternary complexes with PROTAC-recruited E3 ligases. In contrast, weak PROTAC:target protein affinity can be stabilized by high-affinity target:PROTAC:ligase trimer interactions, leading to efficient degradation. This study highlights design guidelines for generating potent PROTACs as well as possibilities for degrading undruggable proteins immune to traditional small-molecule inhibitors.

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It is commonly abbreviated as: C₁V₁ = C₂V₂