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

## TL;DR

Researchers designed a new dual PI3K/mTOR inhibitor with improved properties for treating cancer, showing promise in leukemia cells.

## Contribution

A novel morpholino-triazine derivative (LASSBio-2337) with dual pan-PI3K/mTOR inhibition and activity against drug-resistant leukemia cells.

## Key findings

- Compound 9a (LASSBio-2337) inhibits PI3K and mTOR with IC50 values of 0.3–5.8 μM.
- It shows cytotoxic effects in drug-resistant leukemia cells while sparing healthy cells.
- The compound has moderate permeability but low metabolic stability, indicating potential for further optimization.

## Abstract

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 5f, a simplified gedatolisib
analog, to generate a novel small subseries of morpholino-triazine
derivatives (9a–f). 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 9a (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, 9a 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.