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Abstract: Akt (PKB) plays a central role in the regulation of cellular antiapoptosis and, thus, is a core intracellular survival factor underlying various human neoplastic diseases. Hence, Akt specific inhibitors create an attractive target for anticancer therapy. We have previously demonstrated that proteins of the TCL1 family (a protooncogene underlying human T cell prolymphocytic leukemia) interact with Akt and functions as Akt kinase coactivators. TCL1 coactivate Akt by binding to its pleckstrin homology domain (Akt-PHD). Then, with the aim to develop an Akt kinase inhibitor, we have hypothesized and verified that a peptide, which spans the Akt binding site (the A β-strand of human TCL1), binds to Akt and modulates Akt kinase activity and its downstream biological responses. Nuclear magnetic studies suggested that Akt_in shares a similar binding site with TCL1, but causes remote conformational changes on the variable loop 1 of the PH domain, the locus mediating phosphoinositide binding. In the present paper, we used NMR titration experiments to demonstrate that the binding of Akt-in to Akt-PHD significantly decreases the affinity of the PH domain for IP4, the sugar headgroup of phosphatidyl-inositol phosphate lipids, responsible for the membrane anchorage of the kinase and its subsequent activation. To cite this article: V. Ropars et al., C. R. Chimie 9 (2006) . [Copyright &y& Elsevier]