Planning of new heterocyclic compounds targeting class I PI3Ks for cancer therapy

Class I phosphoinositide-3-kinase (PI3K-C1) are considered important therapeutical targets for cancer therapy since its four isoforms (PI3Kα, β, δ, and γ) are associated with diverse neoplastic manifestations. The first PI3K inhibitor approved by the FDA for cancer therapy, Idelalisib, has great selectivity over myeloid-restricted PI3Kδ. This selectivity is assigned to the Idelalisib propeller-shaped conformation on the active site, having a minimal effect over the ubiquitously expressed PI3Kα. This feature turns Idelalisib a lead compound for developing new PI3Kδ inhibitors. Based on that, this work aims to design and conduct preliminary virtual screening of new heterocyclic compounds for application in cancer therapy. In this sense, 40 compounds that are structurally related to Idelalisib were designed using the concept of bioisosterism. Afterward, the designed molecules were submitted to docking studies over PI3Kδ on Autodock 4.0. The docking protocol was validated with the redocking technique using the complexed ligand LASW1976. The Lowest Binding Energy (LBE) and H-bond profile on the active site were used as parameters for preliminary virtual screening. Idelalisib was also docked to be used as a positive control. 9 out of the 40 designed molecules presented LBE values (-8.10 to -9.95 Kcal/mol) close to Idelisib’s (-9,54 Kcal/mol), and among them, 7 reproduced at least 1 H-bond observed on Idelalisib or LASW1976 on the active site. These results indicate the potential of these 9 compounds to inhibit PI3Kδ, which will be synthesized and biologically evaluated in follow-up studies.