1. Brain-restricted mTOR inhibition with binary pharmacology
- Author
-
Kevin Lou, Ziyang Zhang, Kevan M. Shokat, Xujun Luo, William A. Weiss, and Qi-Wen Fan
- Subjects
Drug ,General Science & Technology ,media_common.quotation_subject ,Central nervous system ,Tacrolimus Binding Protein 1A ,Pharmacology ,Ligands ,Rare Diseases ,Drug Therapy ,medicine ,Humans ,Adverse effect ,PI3K/AKT/mTOR pathway ,media_common ,Cancer ,Sirolimus ,Multidisciplinary ,Kinase ,business.industry ,TOR Serine-Threonine Kinases ,Neurosciences ,Brain ,MTOR Inhibitors ,Ligand (biochemistry) ,medicine.disease ,Xenograft Model Antitumor Assays ,Brain Disorders ,Brain Cancer ,medicine.anatomical_structure ,FKBP ,Orphan Drug ,5.1 Pharmaceuticals ,Combination ,Neurological ,Drug Therapy, Combination ,Development of treatments and therapeutic interventions ,business ,Glioblastoma - 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