Recent studies report the overexpression of protein kinase B PKB/AKT in many human cancers, making AKT a promising and attractive therapeutic target in anticancer drug development. A new ATP-competitive AKT inhibitor <b>1</b>, active in micromolar concentration, has recently been found. This compound presents a different scaffold with respect to other published AKT inhibitors. In order to identify new compounds with biological activity based on <b>1</b>, we started a hit-to-lead optimization, the first step in this process was a computational analysis of a designed database, then, a series of 2,4,6-trisubstituted pyridines were proposed using docking-based virtual screening and molecular dynamics simulation, once computational hits were identified, compounds with safe pharmacological profile were synthetized. To begin this process, 4-amino-2,6-dichloropyridine was used as starting material and a Buckwald-Hatwig coupling was carried out using different compounds containing bromine, then, a Suzuki-Miyaura coupling was performed with the appropriate boronic ester and the designed computational hits were obtained with good yields. The evaluation of the selected compounds against different cell lines and directly on AKT will be presented

First steps in hit-to-lead optimization towards AKT inhibition

253rd National Meeting (2017)

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