Planning and synthesis of novel PI3K/mTOR double inhibitors and applications in neurodegeneration studies

Abstract

The phosphoinositide 3-kinase (PI3K)/alpha-serine/ protein kinase B (Akt)/mammalian rapamycin target (mTOR) pathway, better known as PI3K/Akt/mTOR, is an important intracellular signaling pathway directly related to the control of cell cycle, and consequently to various pathologies related to aging and longevity, such as cancer, type 2 diabetes (DM2), heart disease and neurodegenerative disease (Alzheimer's and Parkinson's disease). Thus, recent studies have emphasized that this pathway's inhibition may be an interesting strategy for the treatment of age-related pathologies. Selective inhibitors for mTORC1 subunit of the multiprotein complex mTOR (rapamycin and rapalogs) presented partial inhibition of mTOR pathway, being not effective in tumor regression. There is also in the literature the description of mTOR (mTORC1 and mTORC2) and PI3K selective inhibitors used in the attempt to modulate this cellular pathway, however with some disadvantages like toxicity. Thus, dual inhibitors of PI3K/mTOR have been developed, and this double inhibition blocks the phosphorylation of dowstream proteins in the signaling pathway in diverse steps, thereby inhibiting cell proliferation in several cell lines inducing the processes of apoptosis and autophagy. However, despite of being effective, these derivatives have not managed to overcome some disadvantages such as low efficacy against some types of cancer, need for use in combination therapy and occurrence of side effects. In this context, the present project proposes the planning and synthesis of potential inhibitors of the PI3K/Akt/mTOR pathway by the concomitant blockade of the three associated targets, PI3K, mTORC1 and mTORC2, for potential prevention and treatment of aging-related neurodegeneration. The proposed structures (derivatives of classes 1 and 2) were obtained from pharmacophoric models generated by the overlapping of potent PI3K/mTOR inhibitors by the Discovery Studio and PharmaGist programs. Both classes have a rigid system of three fused heterocyclic rings, with the possibility to provide great structural diversity by varying the reagents used, in this case, the amino acids (natural, synthetic or of the "D" series) and/or the heterocyclic (imidazole-4-carboxylic acid or 2-amino nicotinic acid). Virtual docking simulations for understanding the possible mode of binding between the obtained compounds and the active sites (PI3K and mTOR) as well as structural optimization of these possible inhibitors will be carried out with the program GOLD 3.1.1. After obtaining these derivatives, they will undergo biological assays in collaboration with Prof. Elza Tiemi Sakamoto Hojo, from the Medical School of Ribeirão Preto (FMRP/USP). (AU)