ACTIONS OF NEW COMPOUNDS INHIBITORS OF AKT IN NORMAL SKELETAL MUSCLE CELLS

A. PAULA IRAZOQUI; CINTIA A. MENÉNDEZ; SEBASTIAN STEINGRUBER; SANTIAGO A. STABILE; DARÍO C. GERBINO; GUSTAVO A. APPIGNANESI; CLAUDIA BUITRAGO

Bariloche

Simposio; Fourth ?South American Spring Symposium in Signal Transduction and Molecular Medicine? (SISTAM 2018); 2018

Universidad de Buenos Aires

Akt (also called PKB) is a serine/threonine kinase family with key implications in proliferation, survival, differentiation, and viability of muscle cells. The mechanism of activation of Akt is complex and has not been fully elucidated. In response to growth factors, Akt upregulation depends on previous PI3K activation. The PI3K/Akt pathway is a therapeutic target that represents an attractive and important alternative for the development of new antitumor agents. Role of PI3K/Akt in proliferation and differentiation of skeletal muscle cells of C2C12 cell line was previously established in our laboratory.The present proposal involves the design, synthesis and biological evaluation of new Akt inhibitors (called IIa and IIb) whose central structure is based on the privileged scaffold dibenzo-4-pyrone, structurally related to commercial inhibitors of PI3K-Akt, LY294002 and quercetin. The efficient construction of the pharmacophore unit takes place by condensation of ortho-substituted benzoic acid and phloroglucinol, using ZnCl2 as the dehydrating agent. The appropriate functional is achieved from transformations of O-alkylation, amination and click reaction. In order to understand the main interactions between the new chemical entities and the molecular target PI3K, simulations were carried out by molecular docking (Autodock4), predominantly detecting interactions of hydrophobic type, highlighting in particular, -stacking interactions with the amino acids Trp 812 and Tyr 867. To test the biological actions of new compounds in live cells, we developed western blot assays in monolayers cultures of proliferating skeletal muscle cells of C2C12 line. Both IIa and IIb inhibited successfully Akt activation. Moreover, these compounds did not exert toxic actions in C2C12 cells in all conditions used, as revealed cellular survival experiments. Our discoveries prompt us into the next studies of these compounds actions in cancer cells.