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

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

  • ACS Omega. 2026 Feb 5;11(6):9719-9733. doi: 10.1021/acsomega.5c10162.
Cristiane Aparecida E Silva 1 2,  Raysa Magali Pillpe-Meza 1 2,  Wesley Leandro Gouveia 1 2,  Joana D'Arc da Silva Trindade 3,  Gisele Barbosa 1,  Amanda Marques Seixas Vieira 3,  Heber Victor Tolomeu 1,  Rayane França Pereira 3,  Carlos Antônio do Nascimento Santos 3,  Leonardo Freire-de-Lima 3,  Lidia Moreira Lima 1 2
Affiliations

Affiliations

  • 1 Laboratório de Avaliação E Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Cidade Universitária, Rio de Janeiro, Rio de Janeiro CEP 21941-902, Brasil.
  • 2 Programa de Pós-Graduação Em Farmacologia E Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Cidade Universitária, Rio de Janeiro, Rio de Janeiro CEP 21941-902, Brasil.
  • 3 Laboratório de Glicobiologia (LABGLICO), Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Cidade Universitária, Rio de Janeiro, Rio de Janeiro CEP 21941-902, Brasil.
PMID: 41726721 DOI: 10.1021/acsomega.5c10162
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.

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