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

The allosteric inhibitor of the mechanistic
target of rapamycin
(mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC)
patients through partial inhibition of mTOR functions. Due to its
limited brain permeability, we sought to develop a catalytic mTOR
inhibitor optimized for central nervous system (CNS) indications.
We recently reported an mTOR inhibitor (1) that is able
to block mTOR functions in the mouse brain and extend the survival
of mice with neuronal-specific ablation of the Tsc1 gene. However, 1 showed the risk of genotoxicity in vitro. Through structure–activity relationship
(SAR) optimization, we identified compounds 9 and 11 without genotoxicity risk. In neuronal cell-based models
of mTOR hyperactivity, both corrected aberrant mTOR activity and significantly
improved the survival rate of mice in the Tsc1 gene
knockout model. Unfortunately, 9 and 11 showed
limited oral exposures in higher species and dose-limiting toxicities
in cynomolgus macaque, respectively. However, they remain optimal
tools to explore mTOR hyperactivity in CNS disease models.