Description
IPA-3 (42521-82-4) is a selective allosteric inhibitor of Group 1 p21-activated kinase (PAK1 IC50= 2.5 μM)1via covalent binding to the PAK1 regulatory domain preventing binding to the upstream activator Cdc422. IPA-3 has been shown to induce cell death in human leukemic cell lines3, significantly inhibit TGFβ1-induced prostate cell epithelial to mesenchymal transition4and inhibit the growth of liver cancer cells5.
Uses
Acts as an allosteric inhibitor of Pak1
Uses
p21-activated kinase 1 (PAK1) is a member of a family non-receptor serine/threonine kinases that are vital to normal cell function. Binding of various upstream partners to PAK1 results in release of an autoinhibitory domain that blocks activity of the kinase domain. PAK1 expression and activity is upregulated in several human cancers and is a potential therapeutic target for cancer intervention. IPA-3 is a cell-permeable allosteric inhibitor of PAK1 that is non-competitive with respect to ATP binding (IC50 = 2.5 μM). It does not, however, inhibit the activity of PAK1 that has been pre-activated with Cdc42. IPA-3 binds covalently to the PAK1 regulatory domain (apparent Kd = 1.9 uM) and prevents binding to the upstream activator Cdc42.[Cayman Chemical]
Definition
ChEBI: An organic disulfide obtained by oxidative dimerisation of 1-sulfanylnaphthalen-2-ol.
Biological Activity
IPA-3 is a selective non-ATP competitive Pak1 inhibitor with IC50 of 2.5 μM in a cell-free assay, no inhibition to group II PAKs (PAKs 4-6).
Biochem/physiol Actions
IPA-3 is an allosteric inhibitor of Pak1. It binds to autoinhibitory domain of Pak1 (p21 activated kinase), highly selective amongst kinases. Pak1 is implicated in tumorigenesis and metastasis.
in vitro
IPA-3 is a non ATP-competitive, allosteric inhibitor of p21-activated kinase 1 (Pak1). PIR3.5 is the control compound of IPA-3. IPA-3 prevents Cdc42-stimulated Pak1 autophosphorylation on Thr423. IPA-3 also prevents sphingosine-dependent Pak1 autophosphorylation. IPA-3 does not target exposed cysteine residues on Pak1. The disulfide bond of IPA-3 is critical for inhibition of Pak1 and in vitro reduction by the reducing agent dithiothreitol (DTT) abolishes Pak1 inhibition by IPA-3. IPA-3 inhibits activation of Pak1 by diverse activators, but does not inhibit preactivated Pak1. IPA-3 inhibits PDGF-stimulated Pak activation in mouse embryonic fibroblasts. IPA-3 inhibits Pak1 activation in part by binding covalently to the regulatory domain of Pak1. IPA-3 binds Pak1 covalently in a time- and temperature-dependent manner. IPA-3 prevents binding of the Pak1 activator Cdc42. IPA-3 binds directly to the Pak1 autoregulatory domain. IPA-3 reversibly inhibits PMA-induced membrane ruffling in cells.
References
[1] SEAN W DEACON. An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase.[J]. Chemistry & biology, 2008, 15 4: 322-331. DOI:
10.1016/j.chembiol.2008.03.005[2] JULIEN VIAUD J R P. An allosteric kinase inhibitor binds the p21-activated kinase autoregulatory domain covalently.[J]. Molecular Cancer Therapeutics, 2009, 8 9: 2559-2565. DOI:
10.1158/1535-7163.mct-09-0102[3] KATEŘINA KUŽELOVÁ. Group I PAK inhibitor IPA-3 induces cell death and affects cell adhesivity to fibronectin in human hematopoietic cells.[J]. PLoS ONE, 2014: e92560. DOI:
10.1371/journal.pone.0092560[4] AHMAD AL-AZAYZIH Payaningal R S Fei Gao. P21 activated kinase-1 mediates transforming growth factor β1-induced prostate cancer cell epithelial to mesenchymal transition[J]. Biochimica et biophysica acta. Molecular cell research, 2015, 1853 5: Pages 1229-1239. DOI:
10.1016/j.bbamcr.2015.02.023[5] LEO LAP-YAN WONG. IPA-3 inhibits the growth of liver cancer cells by suppressing PAK1 and NF-κB activation.[J]. PLoS ONE, 2013: e68843. DOI:
10.1371/journal.pone.0068843
