On-target-off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window of drug candidates. In diseases of the central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition of mTOR while sparing mTOR activity elsewhere through the use of a brain-permeable mTOR inhibitor RapaLink-1 and 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.  ### Competing Interest Statement The authors have declared no competing interest.

Download data

• Downloaded 1,336 times
• Download rankings, all-time:
  • Site-wide: 20,965
  • In cancer biology: 497
• Year to date:
  • Site-wide: 28,738
• Since beginning of last month:
  • Site-wide: 19,680

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide