NEW 1,3-DIHIDROXYACRIDONE DERIVATES: SYNTHESIS AND EVALUATION AS AKT INHIBITORS OF SIGNALING PATHWAY IN SKELETAL MUSCLE CELLS

AGUSTINA GONZALEZ; A. PAULA IRAZOQUI; CINTIA A. MENÉNDEZ; H. SEBASTIÁN STEINGRUBER; APPIGNANESI GUSTAVO; BUITRAGO CLAUDIA; GERBINO DARÍO

Congreso; SAIC reunión anual; 2022

Akt is up-regulated by the previous activation of phosphoinositide 3-kinase (PI3K) in response to growth factors. PI3K phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) generating phosphatidylinositol 3,4,5-trisphosphate (PIP3). The binding of Akt N-terminal pleckstrin homology domain with PIP3 allows for Akt translocation to the plasma membrane. Once there, 3-phosphoinositide-dependent kinase-1 (PDK1) phosphorylates Akt in Thr-308 and PDK1 or PDK2 phosphorylates its Ser-473 residue, promoting the completely Akt activation, so specific antibodies against phospho Ser-473 of Akt only recognize active Akt 1. Due to the intracellular functions of Akt as a pivotal point of converging signalling pathways involved in cell growth, proliferation, apoptosis and neo angiogenesis, the Akt signalling cascade inhibition is being considered as potent anticancer target 2. The skeletal muscle cell line C2C12 is a good model of (non-cancerous) muscle cells. In these cells, Akt is a target of PI3K and the inhibitor LY294002 successfully suppresses Akt Ser-473 phosphorylation 3. RD is a rhabdomyosarcoma (RMS) cell line. Pediatric bone and soft tissue sarcomas often display increased Akt phosphorylation through up regulation of insulin-like growth factor (IGF1) signaling. Additionally, Akt signaling has been linked to resistance to IGF1 receptor (IGF1R) and mTOR (mammalian target of rapamycin) inhibitors in sarcoma, further demonstrating the role of Akt in tumor survival. This suggests targeting components of the PI3K/Akt pathway may be an effective therapeutic strategy 4. The inhibitor LY294002 is a morpholine-containing chemical compound known as a potent inhibitor of numerous proteins, but of relevance, it is a strong inhibitor of PI3K/Akt 5. Results of a meta-analysis of 46 randomized control trials have shown that PI3K/Akt/mTOR pathway inhibitor-based therapies significantly improve the survival of patients with advanced solid tumours 6. In view of this, the role of PI3K/PDK1/Akt inhibitors for human medicine has become highly relevant. Although there are commercial compounds that inhibit PI3K/PDK1/Akt cascade without causing cytotoxic effects in normal cells, such compounds are photosensitive and not fully specific. An interesting strategy applied to the discovery of new drugs consists in the use of the so-called "privileged structures". As such, rigid heterocyclic fragments that possess high affinity for many biological targets are meant. It is noteworthy to mention that the position and the nature of the substituent on the heterocyclic core are determinants for the biological property and selectivity. A promising source of scaffolds to design bioactive molecules are the acridone derivatives and their congeners, which are of great therapeutic interest due to their proven activity in very diverse biological contexts 7?11.This family of fused heterocycles is highly versatile in terms of biological activity, due to its molecular architecture based on a hydrophobic skeleton with the possibility of multiple functionalization sites. In recent years, the development of acridone derivatives as effective anticancer drug candidates has attracted considerable attention 11,12. Considering the experience of our research group in the design, synthesis and biological assays of fused tricyclic heterocycles 1314, here we investigate the synthesis and biological action of four new promising Akt inhibitors based on the acridin-9(10H)-one scaffold (named AC4M (3a), AC5DE (3b), AC5M (3c) and AC6M (3d)). Akt inhibitory activity assays were developed in C2C12 normal skeletal muscle cells and RD rhabdomyosarcoma (RMS) cells.