Design and synthesis of chemical probes for the protein kinase B PH domain

Abstract

Phosphatidyl D-myo-inositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] contributes to the activation of protein kinase B (PKB) by interacting with the PKB PH domain. PKB is known to be up-regulated in several cancer cell types. Compounds that can display selective inhibition of this kinase have promising chemotherapeutic potential, and inhibition of the PH domain of PKB represents a realistic means by which to achieve this. Analysis of the X-ray crystal structures of apo PKBαPH and PKBαPH bound to D-myo-inositol 1,3,4,5-tetrakisphosphate [InsP4, the inositol head group of PtdIns(3,4,5)P3] led to the design of PtdIns(3,4,5)P3 and InsP4 analogues as potential PKB PH domain inhibitors. The synthesis of PtdIns(3,4,5)P3 analogues modified at the C-4 position was investigated, but it was discovered that such compounds were prone to migration of the 1-position phosphate. Subsequently, a range of racemic InsP4 analogues, modified at the C-1 or C-4 position, were successfully synthesised. Advanced progress has also been made towards the synthesis of enantiomerically pure analogues of InsP4.