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.
