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Brain-restricted mTOR inhibition with binary pharmacology

Author

Listed:
  • Ziyang Zhang

    (University of California)

  • Qiwen Fan

    (Helen Diller Family Comprehensive Cancer Center
    University of California)

  • Xujun Luo

    (Helen Diller Family Comprehensive Cancer Center
    University of California)

  • Kevin Lou

    (University of California)

  • William A. Weiss

    (Helen Diller Family Comprehensive Cancer Center
    University of California
    University of California
    University of California)

  • Kevan M. Shokat

    (University of California)

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.

Suggested Citation

  • Ziyang Zhang & Qiwen Fan & Xujun Luo & Kevin Lou & William A. Weiss & Kevan M. Shokat, 2022. "Brain-restricted mTOR inhibition with binary pharmacology," Nature, Nature, vol. 609(7928), pages 822-828, September.
    • Handle: RePEc:nat:nature:v:609:y:2022:i:7928:d:10.1038_s41586-022-05213-y
    DOI: 10.1038/s41586-022-05213-y
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