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

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.