Brain-restricted mTOR inhibition with binary pharmacology

Ziyang Zhang, Qiwen Fan, Xujun Luo, Kevin Lou, William A. Weiss and Kevan M. Shokat ()
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Ziyang Zhang: University of California
Qiwen Fan: Helen Diller Family Comprehensive Cancer Center
Xujun Luo: Helen Diller Family Comprehensive Cancer Center
Kevin Lou: University of California
William A. Weiss: Helen Diller Family Comprehensive Cancer Center
Kevan M. Shokat: University of California

Nature, 2022, vol. 609, issue 7928, 822-828

Abstract: Abstract On-target–off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window of drug candidates1,2. 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.

Date: 2022
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DOI: 10.1038/s41586-022-05213-y

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