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Updated: Feb 24, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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New Dual Pan-PI3K/mTOR Inhibitor: Design, Synthesis, Cytotoxic Action, Permeation, Metabolic Stability, and In Silico

Cristiane Aparecida E Silva1,2, Raysa Magali Pillpe-Meza1,2, Wesley Leandro Gouveia1,2

  • 1Laboratório 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.

ACS Omega
|February 23, 2026
PubMed

Insights

Researchers modified a cancer drug analog, creating new compounds that inhibit the PI3K/AKT/mTOR pathway. Compound 9a shows promise against leukemia, including drug-resistant types, while sparing healthy cells.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Pharmacology

Background:

  • The PI3K/AKT/mTOR pathway is crucial in cancer development and drug resistance.
  • Existing dual PI3K/mTOR inhibitors like gedatolisib have limitations such as poor solubility and metabolic stability.

Purpose of the Study:

  • To explore structural modifications of a gedatolisib analog (compound 5f) to develop novel morpholino-triazine derivatives.
  • To enhance molecular interactions, improve isoform selectivity, and evaluate pharmacological properties of new compounds for cancer therapy.

Main Methods:

  • Synthesis of novel morpholino-triazine derivatives (compounds 9a-f).
  • In vitro evaluation of dual PI3K/mTOR inhibitory activity and cytotoxicity in cancer cell lines.
  • Assessment of selectivity, multidrug resistance phenotype activity, and preliminary pharmacokinetic properties (permeability, metabolic stability).

Main Results:

  • Compound 9a (LASSBio-2337) demonstrated potent dual pan-PI3K/mTOR inhibition.
  • Compound 9a exhibited significant cytotoxicity against leukemia cell lines, including multidrug-resistant phenotypes, with minimal impact on normal human peripheral blood mononuclear cells (hPBMCs).
  • Despite aqueous insolubility, compound 9a showed moderate PAMPA-GIT permeability and low metabolic stability, indicating potential for lead optimization.

Conclusions:

  • Compound 9a represents a promising lead for developing next-generation PI3K/mTOR inhibitors.
  • The study provides valuable structural and mechanistic insights for optimizing dual PI3K/mTOR inhibitors to overcome challenges in cancer treatment.

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