1627676-59-8

Basic information

• Product Name: PFI-2
• Synonyms: (R)-8-fluoro-N-(1-oxo-1-(pyrrolidin-1-yl)-3-(3-(trifluoromethyl)phenyl)propan-2-yl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide (R)-PFI 2 hydrochloride;PFI-2 HCl;R-PFI-2 HCl;8-fluoro-1,2,3,4-tetrahydro-N-[(1R)-2-oxo-2-(1-pyrrolidinyl)-1-[[3-(trifluoromethyl)phenyl]methyl]ethyl]-6-isoquinolinesulfonamide
• CAS NO: 1627676-59-8
• Molecular Formula: C23H25F4N3O3S
• Molecular Weight: 499.5215128
• Product Categories: Inhibitors
• Mol File: 1627676-59-8.mol
• Article Data: 1

Chemical Properties

• Boiling Point: 642.7±65.0 °C(Predicted)
• Appearance: /
• Density: 1.371±0.06 g/cm3(Predicted)
• Solubility: ≥50 mg/mL in DMSO; ≥1.51 mg/mL in H2O with gentle warming and ultrasonic; ≥8.12 mg/mL in EtOH
• PKA: 8.95±0.20(Predicted)
• CAS DataBase Reference: PFI-2(CAS DataBase Reference)
• NIST Chemistry Reference: PFI-2(1627676-59-8)
• EPA Substance Registry System: PFI-2(1627676-59-8)

Safety Data

• Hazardous Substances Data: 1627676-59-8(Hazardous Substances Data)

Usage

Description

PFI-2 is a potent and selective inhibitor of the lysine methyltransferase SETD7, a protein that plays a significant role in various disease-related pathways. Its ability to inhibit SETD7 makes PFI-2 a potential therapeutic agent for targeting diseases associated with this enzyme.

Uses

Used in Pharmaceutical Industry:
PFI-2 is used as a therapeutic agent for targeting diseases associated with the lysine methyltransferase SETD7. Its inhibition of SETD7 can potentially lead to the development of treatments for various conditions that involve this enzyme in their pathology.
Used in Research Applications:
PFI-2 is used as a research tool for studying the role of SETD7 in cellular processes and disease mechanisms. By inhibiting SETD7, researchers can gain insights into the function of this enzyme and its potential as a therapeutic target for various diseases.
Used in Drug Development:
PFI-2 is used in the development of new drugs that target SETD7 for the treatment of diseases where this enzyme plays a crucial role. Its potent and selective inhibition of SETD7 makes it a valuable starting point for designing and optimizing novel therapeutic agents.

Biological Activity

pfi-2 is a potent and selective inhibitor of setd7 methyltransferase with ic50 value of 2.0 nm [1].set domain containing (lysine methyltransferase) 7 (setd7) is a protein lysine methyltransferase that acts as monomethyltransferase of lysine 4 on histone h3 (h3k4) and regulates dna methyltransferase 1 (dnmt1) [1].pfi-2 is a potent and selective setd7 methyltransferase inhibitor. (r)-pfi-2 inhibited human setd7 methyltransferase activity with ic50 value of 2.0 nm. however, (s)-pfi-2 was 500-fold less active with ic50 value of only 1.0 μm. (r)-pfi-2 potently inhibited setd7 with morrison kiapp value of 0.33 nm. (r)-pfi-2 occupied the peptide binding groove and effectively inhibited the binding of setd7 substrates. in the presence of 20 μm sam, (r)-pfi-2 bound to setd7 with kd value of 4.2 nm in a sam-dependent way. in hek293 cells, (r)-pfi-2 (10 μm) bound to and stabilized setd7. in setd7+/+ murine embryonic fibroblasts (mefs), (r)-pfi-2 increased nuclear localization of yes-associated protein (yap) and the expression of yap target genes ctgf, gli2 and cdc20 [1].

Enzyme inhibitor

This SETD7 inhibitor (FW = 499.52 g/mol; CAS 1627676-59-8; IUPAC: 8- fluoro-1,2,3,4-tetrahydro-N-[(1R)-2-oxo-2-(1-pyrrolidinyl)-1-[[3- (trifluoromethyl)phenyl]methyl]ethyl]-6-isoquinolinesulfonamide, targets the SET domain containing lysine methyltransferase, or SETD7 (Ki = 0.33 nM; IC50 = 2 nM), showing 1000-times selectivity versus other methyltransferases and other non-epigenetic targets. (R)-PFI-2 exhibits an unusual cofactor-dependent and substrate-competitive inhibitory mechanism by occupying the substrate peptide binding groove of SETD7, including the catalytic lysine-binding channel, and by making direct contact with the donor methyl group of the cofactor, S-adenosylmethionine. In murine embryonic fibroblasts, (R)-PFI-2 treatment phenocopies the effects of Setd7 deficiency on Hippo pathway signaling, via modulation of the transcriptional coactivator Yes-associated protein (YAP) and regulation of YAP target genes. In confluent MCF7 cells, (R)-PFI-2 rapidly alters YAP localization, suggesting continuous and dynamic regulation of YAP by the methyltransferase activity of SETD7.

references

[1]. barsyte-lovejoy d, li f, oudhoff mj, et al. (r)-pfi-2 is a potent and selective inhibitor of setd7 methyltransferase activity in cells. proc natl acad sci u s a, 2014, 111(35): 12853-12858.

Upstream product

• 82317-82-6 ((R)-2-(tert-butoxycarbonyl)amino)-3-(3-(trifluoromethyl)phenyl)propanoic acid 
• 57848-46-1 4-bromo-2-fluorobenzaldehyde 
• 1183945-15-4 N-(4-bromo-2-fluorobenzyl)-2,2-dimethoxyethan-1-amine 
• 1613147-81-1 tert-butyl 6-bromo-8-fluoro-1,2,3,4,-tetrahydroisoquinoline-2(1H)-carboxylate 
• 1339780-81-2 6-bromo-8-fluoro-1,2,3,4-tetrahydroisoquinoline 
• 1258833-77-0 6-bromo-8-fluoroisoquinoline 

Relevant articles and documents

Structure–Activity Relationship Studies on (R)-PFI-2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7

SETD7 is a histone H3K4 lysine methyltransferase involved in human gene regulation. Aberrant expression of SETD7 has been associated with various diseases, including cancer. Therefore, SETD7 is considered a good target for the development of new epigenetic drugs. To date, few selective small-molecule inhibitors have been reported that target SETD7, the most potent being (R)-PFI-2. Herein we report structure–activity relationship studies on (R)-PFI-2 and its analogues. A library of 29 structural analogues of (R)-PFI-2 was synthesized and evaluated for inhibition of recombinantly expressed human SETD7. The key interactions were found to be a salt bridge and a hydrogen bond formed between (R)-PFI-2′s NH2+ group and SETD7′s Asp256 and His252 residue, respectively.