Development of new @entity2856 kinase inhibitors using XXXX mimics.

@entity10175 @entity0 @entity5 @entity442 @entity2856 @entity669 @entity72880 @entity855 @entity6153
Because @entity442 ( @entity442 ) and its receptor play a pivotal role in many @entity5 , it is an attractive target for the design of inhibitors. Here we present a new family of bioisostere inhibitors, based on the structure of @entity72880 . @entity72880 is a substrate-competitive inhibitor of the @entity2856 ( @entity2856 ), with an IC50 = 61 nM in a cell-free kinase assay (Blum, G., Gazit, A., and Levitzki, A. (2000) Biochemistry 39, 15705-15712). @entity72880 is a low molecular weight compound containing two @entity6153 rings, which are sensitive to oxidation in cells. We have therefore prepared and examined @entity6153 bioisosteres of @entity72880 . These @entity72880 bioisosteres possess similar biological properties to @entity72880 ; they inhibit @entity2856 by a substrate-competitive mechanism and are non-competitive vis    vis @entity855 . They inhibit @entity2856 kinase activity in the sub-micromolar concentration range in cell-free assays. @entity442 induced @entity2856 autophosphorylation; @entity10175 phosphorylation and protein kinase B activation are inhibited at a low micromolar concentration range when applied to intact cells. These inhibitors also block the formation of colonies in soft agar by prostate and @entity0 cells. The ability to replace @entity6153 groups with a moiety that is more stable in cells may aid in developing non- @entity6153 -containing substrate-competitive inhibitors targeted toward @entity2856 and possibly against other protein- @entity669 kinases.
