Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Brain-Restricted mTOR Inhibition with Binary Pharmacology

View ORCID ProfileZiyang Zhang, Qiwen Fan, Xujun Luo, Kevin J. Lou, William A. Weiss, View ORCID ProfileKevan M. Shokat
doi: https://doi.org/10.1101/2020.10.12.336677
Ziyang Zhang
1Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Ziyang Zhang
Qiwen Fan
2Helen Diller Family Comprehensive Cancer Center, San Francisco, California
3Department of Neurology, University of California, San Francisco, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xujun Luo
2Helen Diller Family Comprehensive Cancer Center, San Francisco, California
3Department of Neurology, University of California, San Francisco, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevin J. Lou
1Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
William A. Weiss
2Helen Diller Family Comprehensive Cancer Center, San Francisco, California
3Department of Neurology, University of California, San Francisco, California
4Department of Pediatrics, University of California, San Francisco, California
5Department of Neurological Surgery, University of California, San Francisco, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kevan M. Shokat
1Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Kevan M. Shokat
  • For correspondence: kevan.shokat@ucsf.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

On-target-off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window of drug candidates. In diseases of the central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition of mTOR while sparing mTOR activity elsewhere through the use of a brain-permeable mTOR inhibitor RapaLink-1 and 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted October 12, 2020.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Brain-Restricted mTOR Inhibition with Binary Pharmacology
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Brain-Restricted mTOR Inhibition with Binary Pharmacology
Ziyang Zhang, Qiwen Fan, Xujun Luo, Kevin J. Lou, William A. Weiss, Kevan M. Shokat
bioRxiv 2020.10.12.336677; doi: https://doi.org/10.1101/2020.10.12.336677
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Brain-Restricted mTOR Inhibition with Binary Pharmacology
Ziyang Zhang, Qiwen Fan, Xujun Luo, Kevin J. Lou, William A. Weiss, Kevan M. Shokat
bioRxiv 2020.10.12.336677; doi: https://doi.org/10.1101/2020.10.12.336677

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cancer Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (4655)
  • Biochemistry (10307)
  • Bioengineering (7618)
  • Bioinformatics (26203)
  • Biophysics (13453)
  • Cancer Biology (10625)
  • Cell Biology (15348)
  • Clinical Trials (138)
  • Developmental Biology (8456)
  • Ecology (12761)
  • Epidemiology (2067)
  • Evolutionary Biology (16777)
  • Genetics (11361)
  • Genomics (15407)
  • Immunology (10556)
  • Microbiology (25060)
  • Molecular Biology (10162)
  • Neuroscience (54128)
  • Paleontology (398)
  • Pathology (1655)
  • Pharmacology and Toxicology (2877)
  • Physiology (4315)
  • Plant Biology (9204)
  • Scientific Communication and Education (1582)
  • Synthetic Biology (2543)
  • Systems Biology (6753)
  • Zoology (1453)