Brain-restricted mTOR inhibition with binary pharmacology

  • Nature. 2022 Sep;609(7928):822-828. doi: 10.1038/s41586-022-05213-y.
Ziyang Zhang  1 ,  Qiwen Fan  2  3 ,  Xujun Luo  2  3 ,  Kevin Lou  1 ,  William A Weiss  2  3  4  5 ,  Kevan M Shokat  6
Affiliations
  • 1. Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, USA.
  • 2. Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
  • 3. Department of Neurology, University of California, San Francisco, CA, USA.
  • 4. Department of Pediatrics, University of California, San Francisco, CA, USA.
  • 5. Department of Neurological Surgery, University of California, San Francisco, CA, USA.
  • 6. Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA, USA. [email protected].
PMID: 36104566 DOI: 10.1038/s41586-022-05213-y
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.

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