PT  - JOURNAL ARTICLE
AU  - Ziyang Zhang
AU  - Qiwen Fan
AU  - Xujun Luo
AU  - Kevin J. Lou
AU  - William A. Weiss
AU  - Kevan M. Shokat
TI  - Brain-Restricted mTOR Inhibition with Binary Pharmacology
AID  - 10.1101/2020.10.12.336677
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.12.336677
4099  - http://biorxiv.org/content/early/2020/10/12/2020.10.12.336677.short
4100  - http://biorxiv.org/content/early/2020/10/12/2020.10.12.336677.full
AB  - 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 StatementThe authors have declared no competing interest.