Medicinal chemistry efforts towards the identification and development of inhibitors of phosphatidylinositol 3-kinases (PI3Ks) and related protein kinases for cancer treatment

3953 Constitutive activation of the PI3K/Akt pathway seems to be a prerequisite for a wide spectrum of cancers, either by loss / mutations of PTEN, acquisition of activating mutations in the PI3K catalytic subunit, or amplification / overexpression of receptor tyrosine kinases upstream of PI3K. In this respect, PI3K/Akt pathway components such as members of the class I PI3Ks represent well validated molecules for the discovery and development of targeted anticancer drugs. Although they have sub-optimal pharmaceutical properties, PI3K inhibitors like the fungal metabolite wortmannin and the morpholino derivative LY294002 have shown that this class of lipid kinases is drug-able. This poster is disclosing our medicinal chemistry efforts to identify and optimize new pan class I PI3K inhibitors using the privilege kinase inhibitor scaffold imidazo[4,5-c]quinoline. From extensive structure activity relationship and in vivo studies, a clinical candidate has been selected from this chemotype. This PI3K inhibitor, which has suitable pharmacological properties for clinical development, shows an efficient control of the PI3K/Akt pathway in tumor cells by inhibiting the phosphorylation of Akt in cellular and in vivo settings.