Brain-restricted mTOR inhibition with binary pharmacology

On-target-off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window of drug candidates(1,2). In diseases of the central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition of mammalian target of rapamycin (mTOR) while sparing mTOR activity elsewhere through the use of the brain-permeable mTOR inhibitor RapaLink-1 and the brain-impermeable FKBP12 ligand RapaBlock. We show that this drug combination mitigates the systemic effects of mTOR inhibitors but retains the efficacy of RapaLink-1 in glioblastoma xenografts. We further present a general method to design cell-permeable, FKBP12-dependent kinase inhibitors from known drug scaffolds. These inhibitors are sensitive to deactivation by RapaBlock, enabling the brain-restricted inhibition of their respective kinase targets.

Automated summary

This study presents a strategy to achieve brain-specific treatment of central nervous system diseases by combining brain-permeable and brain-impermeable drugs. The design of cell-permeable FKBP12-dependent kinase inhibitors enables brain-restricted inhibition of specific kinase targets.