Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes.

Area of Science:

• Pharmacology
• Neuroscience
• Drug Discovery

Background:

• Tuberous sclerosis complex (TSC) involves mTOR hyperactivity, leading to seizures.
• Current treatments like everolimus have limited brain penetration.
• Developing CNS-optimized mTOR inhibitors is crucial for TSC and other neurological disorders.

Purpose of the Study:

• To develop novel catalytic mTOR inhibitors for CNS indications.
• To identify compounds with improved brain permeability and reduced genotoxicity compared to earlier candidates.
• To evaluate the efficacy and safety of new inhibitors in preclinical models of mTOR hyperactivity.

Main Methods:

• Structure-activity relationship (SAR) optimization of an initial mTOR inhibitor (compound 1).
• In vitro genotoxicity assessment of optimized compounds.
• Evaluation in neuronal cell-based models of mTOR hyperactivity.
• Assessment of efficacy in a mouse model of TSC (Tsc1 gene knockout).
• Pharmacokinetic and toxicology studies in higher species and non-human primates.

Main Results:

• Identified compounds 9 and 11 with no in vitro genotoxicity risk.
• Compounds 9 and 11 corrected aberrant mTOR activity in neuronal models.
• Both compounds improved survival rates in the Tsc1 knockout mouse model.
• Compound 9 exhibited limited oral exposure in higher species.
• Compound 11 showed dose-limiting toxicities in cynomolgus macaques.

Conclusions:

• Compounds 9 and 11 are valuable tools for studying mTOR hyperactivity in CNS disease models.
• Despite efficacy in preclinical models, challenges in oral exposure and toxicity require further investigation for clinical translation.
• Further optimization is needed to develop safe and effective CNS-penetrant mTOR inhibitors for neurological disorders.