Recent Development of Anticancer Therapeutics Targeting Akt

John      K. Morrow; Lei      Du-Cuny; Lu      Chen; Emmanuelle      J. Meuillet; Eugene      A. Mash; Garth      Powis; Shuxing      Zhang

doi:10.2174/157489211793980079

Abstract

The serine/threonine kinase Akt has proven to be a significant signaling target, involved in various biological functions. Because of its cardinal role in numerous cellular responses, Akt has been implicated in many human diseases, particularly cancer. It has been established that Akt is a viable and feasible target for anticancer therapeutics. Analysis of all Akt kinases reveals conserved homology for an N-terminal regulatory domain, which contains a pleckstrin-homology (PH) domain for cellular translocation, a kinase domain with serine/threonine specificity, and a C-terminal extension domain. These well defined regions have been targeted, and various approaches, including in silico methods, have been implemented to develop Akt inhibitors. In spite of unique techniques and a prolific body of knowledge surrounding Akt, no targeted Akt therapeutics have reached the market yet. Here we will highlight successes and challenges to date on the development of anticancer agents modulating the Akt pathway in recent patents as well as discuss the methods employed for this task. Special attention will be given to patents with focus on those discoveries using computer-aided drug design approaches.

Keywords: Akt, anticancer therapeutics, computer-aided drug design, drug discovery and development, pleckstrin-homology (PH) domain, serine/threonine kinase, pleckstrin-homology, Leu156, Thr211, Glu278, Asn279, PDPK1, myelopoiesis, perifosine, ADMET, SYBYL, surface plasmon resonance spectroscopy, X-ray crystallography, Bevacizumab, Tarceva, Gleevec