Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders

Recent clinical evaluation of everolimus
for seizure reduction
in patients with tuberous sclerosis complex (TSC), a disease with
overactivated mechanistic target of rapamycin (mTOR) signaling, has
demonstrated the therapeutic value of mTOR inhibitors for central
nervous system (CNS) indications. Given that everolimus is an incomplete
inhibitor of the mTOR function, we sought to develop a new mTOR inhibitor
that has improved properties and is suitable for CNS disorders. Starting
from an in-house purine-based compound, optimization of the physicochemical
properties of a thiazolopyrimidine series led to the discovery of
the small molecule 7, a potent and selective brain-penetrant
ATP-competitive mTOR inhibitor. In neuronal cell-based models of mTOR
hyperactivity, 7 corrected the mTOR pathway activity
and the resulting neuronal overgrowth phenotype. The new mTOR inhibitor 7 showed good brain exposure and significantly improved the
survival rate of mice with neuronal-specific ablation of the Tsc1
gene. These results demonstrate the potential utility of this tool
compound to test therapeutic hypotheses that depend on mTOR hyperactivity
in the CNS.