New Dual Pan-PI3K/mTOR Inhibitor: Design, Synthesis, Cytotoxic Action, Permeation, Metabolic Stability, and In Silico Protein-Ligand Interaction.

The PI3K/AKT/mTOR pathway is frequently dysregulated in cancer, contributing to tumor progression, drug resistance, and poor prognosis. Dual PI3K/mTOR inhibitors such as gedatolisib have shown clinical promise, but they still face challenges, including low solubility, poor metabolic stability, and limited activity against resistant tumor phenotypes. Here, we report a proof-of-concept study exploring structural modifications on compound , a simplified gedatolisib analog, to generate a novel small subseries of morpholino-triazine derivatives (-). The goal was to improve molecular interactions within the affinity site of PI3K, investigate the impact on isoform selectivity, and evaluate pharmacological properties relevant to early optimization. Among these, compound (LASSBio-2337) emerged as a dual pan-PI3K/mTOR inhibitor (IC: 0.3-5.8 μM), showing cytotoxic effects in leukemia cell lines (CC: 4.37-9.44 μM), including those with multidrug resistance (Lucena, MDR phenotype), while sparing nontumor hPBMCs. Although aqueous insoluble, displayed moderate PAMPA-GIT permeability and low metabolic stability in rat liver microsomes, underscoring its potential as a lead for further optimization. This integrated study provides structural, mechanistic, and pharmacokinetic insights to guide next-generation PI3K/mTOR inhibitor design.