美国加州大学旧金山分校Kevan M. Shokat研究团队实现大脑限制的mTOR抑制。相关论文于2022年9月14日在线发表在《自然》杂志上。
研究人员报告了一种策略，通过使用脑渗透性mTOR抑制剂RapaLink-1和脑渗透性FKBP12配体RapaBlock，实现对mTOR的抑制，同时在其他地方避免mTOR活性。研究人员表明，这种药物组合减轻了mTOR抑制剂的全身效应，但保留了RapaLink-1在胶质母细胞瘤异种移植中的疗效。研究人员进一步提出了一种通用方法，从已知的药物支架中设计出可渗透细胞的、依赖FKBP12的激酶抑制剂。这些抑制剂对RapaBlock的失活很敏感，能够对其各自的激酶靶点进行大脑限制性抑制。
据悉，靶向-组织外药物接触是制约候选药物治疗窗口的一个重要不良反应来源。在中枢神经系统的疾病中，具有脑部限制药理学的药物是非常理想的。
附：英文原文
Title: Brain-restricted mTOR inhibition with binary pharmacology
Author: Zhang, Ziyang, Fan, Qiwen, Luo, Xujun, Lou, Kevin, Weiss, William A., Shokat, Kevan M.
Issue&Volume: 2022-09-14
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.
DOI: 10.1038/s41586-022-05213-y
Source: https://www.nature.com/articles/s41586-022-05213-y
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
