Design and synthesis of small-molecule stabilizers of protein-protein interactions (PPIs) as a novel class of therapeutic agents and basic reseach tool compounds.

Protein-protein interactions (PPIs) mediate a wide variety of cellular processes, being essential for the regulation of most biological pathways. During the last years, targeting the PPIs complex network has been recognized as an emerging and promising drug discovery strategy for the therapeutic intervention of a number of pathologies. Here, we focus on the 14-3-3 adapter protein PPIs and its modulation through small molecules. This family of conserved proteins is expressed in all eukaryotic cells and maintains essential roles in regulatory processes by binding several hundred identified partners. Due to their involvement in a wide range of physiological and biological events, this protein has been related to numerous diseases, such as cancer and neurodegenerative and metabolic disorders. Despite the great effort made in the modulation of 14-3-3 complexes, only a few successful examples have been reported in the literature being most of them on the disruption of 14-3-3 PPIs. However, the mere identification of these compounds illustrates the feasibility of this approach and encourages the continued development of this discovery strategy. The aim of this thesis is first to provide a summary of the different approaches investigated for the modulation of PPIs and a review of some of the latest examples on inhibition and stabilization with a special focus on the modulation of 14-3-3 adapter protein PPIs. Inside the 14-3-3- PPIs topic, three projects were developed. The first one used the parasitic 14-3-3 as a target, leading to the successful discovery of a family of small molecular inhibitors, considered an innovative strategy for the treatment of tropical neglected diseases. While the second and third ones spotlight the 14-3-3/c-Abl interaction and its relationship with the development of chronic myeloid leukaemia. In this perspective, this thesis has elucidated the 14-3-3 protein as a highly relevant target in drug discovery and proved that modulation of these interactions is a valuable tool for the development of alternative therapies.