1. Brain-restricted mTOR inhibition with binary pharmacology
- Author
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Zhang, Ziyang, Fan, Qiwen, Luo, Xujun, Lou, Kevin, Weiss, William A, and Shokat, Kevan M
- Subjects
Biomedical and Clinical Sciences ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Biological Psychology ,Psychology ,Pharmacology and Pharmaceutical Sciences ,Neurosciences ,Orphan Drug ,Cancer ,Rare Diseases ,Brain Disorders ,Brain Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Neurological ,Humans ,Brain ,Drug Therapy ,Combination ,Glioblastoma ,Ligands ,MTOR Inhibitors ,Sirolimus ,Tacrolimus Binding Protein 1A ,TOR Serine-Threonine Kinases ,Xenograft Model Antitumor Assays ,General Science & Technology - 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.
- Published
- 2022