Multidisciplinary approach for design and synthesis of new therapeutic tools to overcome drug resistance in aggressive tumors

Cancer is a multifaceted disease characterized by a tangled network of oncogenic mechanisms and resistance to therapies and it is a leading cause of death worldwide. Against this background, two potential anti-cancer targets will be described as promising therapeutic approaches: targeting metabolic alterations and dual PDK1/AurA inhibition. The first topic deals with the rational design, supported by docking simulations, of a small library of new G6PDi-1 analogues, an allosteric inhibitor of G6PD protein. So, it will be described the followed synthetic optimization process which led us to obtain twenty new derivatives characterized by diversified scaffolds. Then, preliminary in vitro evaluation of a small series of designed compounds in different cancer cells will be discussed. On the other hand, the second part of this thesis deals with the design and synthesis of new PDK1/AurA dual inhibitors. Following a multidisciplinary approach, the synthesis of new inhibitors together with the safe ADME-Tox profiling and the antiproliferative activity against resistant and aggressive cancer types will be discussed. Finally, an in-dept in vivo PK profile and in silico metabolic prediction of selected PDK1/AurA inhibitor will be presented and described.