Novel Inhibitors of AKT: Assessment of a Different Approach Targeting the Pleckstrin Homology Domain

Abstract

Protein kinase B/AKT plays a central role in cancer. The serine/threonine kinase is overexpressed or constitutively active in many cancers and has been validated as a therapeutic target for cancer treatment. However, targeting the kinase activity has revealed itself to be a challenge due to non-selectivity of the compounds towards other kinases. This review summarizes other approaches scientists have developed to inhibit the activity and function of AKT. They consist of targeting the pleckstrin homology (PH) domain of AKT. Indeed, upon the generation of 3-phosphorylated phosphatidylinositol phosphates (PI3Ps) by PI3-kinase (PI3K), AKT translocates from the cytosol to the plasma membrane and binds to the PI3Ps via its PH domain. Thus, several analogs of PI3Ps (PI Analogs or PIAs), alkylphospholipids (APLs), such as edelfosine or inositol phosphates (IPs) have been described to inhibit the binding of the PH domain to PI3Ps. Recent allostetic inhibitors and small molecules that do not bind the kinase domain but affect the kinase activity of AKT, presumably by interacting with the PH domain, have been also identified. Finally, several drug screening studies spawned novel chemical scaffolds that bind the PH domain of AKT. Together, these approaches have been more or less sucessful in vitro and to some extent translated in preclinical studies. Several of these new AKT PH domain inhibitors exhibit promising anti-tumor activity in mouse models and some of them show synergy with ionizing radiation and chemotherapy. Early clinical trials have started and results will attest to the validity and efficacy of such approaches in the near future.

A 2D-QSAR and Grid-Independent Molecular Descriptor (GRIND) Analysis of Quinoline-Type Inhibitors of Akt2: Exploration of the Binding Mode in the Pleckstrin Homology (PH) Domain

“…However, carbonyl group at the R1 position forms a hydrogen bond with Lys30, as shown in Fig 6A. This is further supported by the finding of Meuillet [73], who demonstrated the interaction of Lys30 with sulfonamide type inhibitors against the PH domain of Akt. Moreover, a different study elucidated that the Lys30 and Lys389 pair is involved in cross-linking between the PH domain and the kinase domain of Akt, thus playing a crucial role in the inter-domain conformational changes during activation and ligand binding [74].…”

Structural and Biophysical Characterization of the Interactions between Calmodulin and the Pleckstrin Homology Domain of Akt

“…Previous studies have shown that the PHDs of Akt and other proteins containing analogous PHD have a propensity to self-associate and form aggregates in solution at protein concentrations required for structural studies (34,(47)(48)(49). Although the oligomerization properties of Akt(PHD) have not been studied in detail, an NMR study revealed that the PHD of dynamin is present in a monomer-dimer equilibrium with a K d of ϳ1 mM (49).…”

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

“…However, MK-2206 is generally well tolerated at doses that result in plasma concentrations portending activity in preclinical models. 40 MK-2206 demonstrated marked anti-leukemic effects in vitro against T-ALL patient lymphoblasts. The cytotoxic effects were specific to leukemic cells, as the drug only slightly affected the proliferation of CD4 þ T lymphocytes from healthy donors.…”