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 <b>5f</b>, a simplified gedatolisib analog, to generate a novel small subseries of morpholino-triazine derivatives (<b>9a</b>-<b>f</b>). 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 <b>9a</b> (LASSBio-2337) emerged as a dual pan-PI3K/mTOR inhibitor (IC₅₀: 0.3-5.8 μM), showing cytotoxic effects in leukemia cell lines (CC₅₀: 4.37-9.44 μM), including those with multidrug resistance (Lucena, MDR phenotype), while sparing nontumor hPBMCs. Although aqueous insoluble, <b>9a</b> 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.