Details

Autor(en) / Beteiligte

• Zhang, Ziyang
• Fan, Qiwen
• Luo, Xujun
• Lou, Kevin
• Weiss, William A.
• Shokat, Kevan M.

Titel

Brain-restricted mTOR inhibition with binary pharmacology

Ist Teil von

• Nature (London), 2022-09, Vol.609 (7928), p.822-828

Ort / Verlag

London: Nature Publishing Group

Erscheinungsjahr

2022

Beschreibungen/Notizen

• Abstract On-target–off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window of drug candidates 1,2 . 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.