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bioRxiv · 10.1101/2020.10.12.336677

Brain-Restricted mTOR Inhibition with Binary Pharmacology

Zhang, Z.·Fan, Q.·Luo, X.·Lou, K. J.·Weiss, W. A.·Shokat, K.
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Abstract

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.

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Zhang, Z., Fan, Q., Luo, X., Lou, K. J., Weiss, W. A., Shokat, K.. 2020-10-12. Brain-Restricted mTOR Inhibition with Binary Pharmacology. https://doi.org/10.1101/2020.10.12.336677

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