1415562-82-1 Usage
Description
PF 543 is a cell-permeable hydroxymethylpyrrolidine compound that acts as a high affinity sphingosine kinase-1/SphK1 substrate inhibitor. It potently inhibits SphK1-catalyzed sphingosine-to-S1P conversion, exhibiting selectivity over SphK2 and no affinity towards S1P receptors or a panel of other lipid and protein kinases.
Uses
Used in Pharmaceutical Industry:
PF 543 is used as a sphingosine kinase-1 inhibitor for its potent inhibitory effects on the conversion of sphingosine to S1P. This makes it a valuable compound for research and development in the pharmaceutical industry, particularly in the area of cancer treatment and other diseases involving sphingolipid metabolism.
Used in Cancer Research:
PF 543 is used as a research tool for studying the role of sphingosine kinase-1 in cancer cell biology. Its ability to inhibit SphK1 activity and deplete intracellular S1P levels can provide insights into the mechanisms of cancer cell growth and survival, potentially leading to the development of novel therapeutic strategies.
Used in Drug Development:
PF 543 is used as a lead compound in the development of new drugs targeting sphingosine kinase-1. Its high selectivity and potency make it an attractive starting point for the design and synthesis of more potent and selective inhibitors, which could be used in the treatment of various diseases, including cancer.
Used in Cell Biology Research:
PF 543 is used as a cell permeable compound to study the effects of intracellular S1P depletion on cell signaling and function. Its ability to modulate sphingolipid metabolism can help researchers understand the role of S1P in cellular processes and identify potential targets for therapeutic intervention.
Used in Human Whole Blood Assays:
PF 543 is used in human whole blood assays to study its activity in the presence of human and bovine serum proteins. This application helps researchers evaluate the compound's potential for use in clinical settings and its effectiveness in modulating sphingolipid metabolism in a more physiologically relevant context.
Biological Activity
pf-543 is a novel and cell-permeant inhibitor of sphingosine kinase (sphk1) with ic50 value of 3.6 nm [1],sphk1 is a kinase that phosphorylates sphingosine to sphingosine-1-phosphate (sip). sphk1 is normally a cytosolic protein but can be recruited to the membrane to conduct its activity. it is the major source of production of s1p which promotes cell growth, survival and migration, and also regulate lymphocyte trafficking.biochemical study has identified that sphk1 was a sphingosine-competitive inhibitor but not atp-competitive [1]. in 1483 head and neck carcinoma cell cultures expressing high levels of sphk1 and with an unusually high rate of s1p production, pretreatment of pf-543 for 1 hr decreased the level of endogenous s1p by 10-fold with a proportional increase in the level of sphingosine. it indicated a significant inhibition of sphk1 by pf-543. however, speci?c inhibition of sphk1 had no effect on the proliferation and survival of 1483 cell cultures, despite a dramatic change in the cellular s1p/sphingosine rate [1].the inhibitory activity of pf-543 was also examined ex vivo in human whole blood. human whole blood with high sphk1 activity was prepared, which was able to quickly convert c17-sphingosine to c17-s1p. pf-543 treatment showed that pf-543 was a potent inhibitor of sphk1, capable of blocking >90% c17-s1p formation [1].
Biochem/physiol Actions
PF-543 hydrochloride is a novel, cell-permeable, potent and selective inhibitor of sphingosine kinase-1 (SphK1). PF-543 inhibits SphK1 with a Ki of 3.6 nM, is sphingosine competitive and is more than 100-fold selective for SphK1 over the SphK2 isoform. PF-543 decreased the level of endogenous S1P by 10-fold with proportional increase of the level of sphingosine.
references
[1] schnute m e et al. , modulation of cellular s1p levels with a novel, potent and specific inhibitor of sphingosine kinase-1. biochem j. 2012, 444(1): 79-88.
Check Digit Verification of cas no
The CAS Registry Mumber 1415562-82-1 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,4,1,5,5,6 and 2 respectively; the second part has 2 digits, 8 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 1415562-82:
(9*1)+(8*4)+(7*1)+(6*5)+(5*5)+(4*6)+(3*2)+(2*8)+(1*2)=151
151 % 10 = 1
So 1415562-82-1 is a valid CAS Registry Number.
1415562-82-1Relevant articles and documents
Discovery of a Potent and Selective Sphingosine Kinase 1 Inhibitor through the Molecular Combination of Chemotype-Distinct Screening Hits
Schnute, Mark E.,McReynolds, Matthew D.,Carroll, Jeffrey,Chrencik, Jill,Highkin, Maureen K.,Iyanar, Kaliapan,Jerome, Gina,Rains, John W.,Saabye, Matthew,Scholten, Jeffrey A.,Yates, Matthew,Nagiec, Marek M.
, p. 2562 - 2572 (2017/04/03)
Sphingosine kinase (SphK) is the major source of the lipid mediator and G protein-coupled receptor agonist sphingosine-1-phosphate (S1P). S1P promotes cell growth, survival, and migration and is a key regulator of lymphocyte trafficking. Inhibition of S1P signaling has been proposed as a strategy for treatment of inflammatory diseases and cancer. Two different formats of an enzyme-based high-throughput screen yielded two attractive chemotypes capable of inhibiting S1P formation in cells. The molecular combination of these screening hits led to compound 22a (PF-543) with 2 orders of magnitude improved potency. Compound 22a inhibited SphK1 with an IC50 of 2 nM and was more than 100-fold selective for SphK1 over the SphK2 isoform. Through the modification of tail-region substituents, the specificity of inhibition for SphK1 and SphK2 could be modulated, yielding SphK1-selective, potent SphK1/2 dual, or SphK2-preferential inhibitors.
