Definition of the binding mode of a new class of phosphoinositide 3-kinase ?-selective inhibitors using in vitro mutagenesis of non-conserved amino acids and kinetic analysis.

ABSTRACT: The binding mechanism of a new class of lipid-competitive, ATP non-competitive, p110? isoform-selective PI3K (phosphoinositide 3-kinase) inhibitors has been elucidated. Using the novel technique of isoform reciprocal mutagenesis of non-conserved amino acids in the p110? and p110? isoforms, we have identified three unique binding mechanisms for the p110?-selective inhibitors PIK-75, A-66S and J-32. Each of the inhibitor's p110?-isoform-selective binding was found to be due to interactions with different amino acids within p110. The PIK-75 interaction bound the non-conserved region 2 amino acid p110? Ser(773), A-66S bound the region 1 non-conserved amino acid p110? Gln(859), and J-32 binding had an indirect interaction with Lys(776) and Ile(771). The isoform reciprocal mutagenesis technique is shown to be an important analytical tool for the rational design of isoform-selective inhibitors.

SUBMITTER: Zheng Z 

PROVIDER: S-EPMC3474370 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature