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.

中文翻译：

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具有二元药理学的脑限制mTOR抑制

组织外靶标药物的结合是不良反应的重要来源，它限制了候选药物的治疗范围。在中枢神经系统疾病中，非常需要具有脑限制药理学的药物。在这里，我们报告了一种策略，该策略可通过使用可渗透脑的mTOR抑制剂RapaLink-1和不可渗透脑的FKBP12配体RapaBlock来实现在抑制mTOR的同时在其他地方保留mTOR活性的策略。我们表明这种药物组合减轻了mTOR抑制剂的全身作用，但保留了RapaLink-1在成胶质细胞瘤异种移植物中的功效。我们进一步提出了从已知药物支架设计细胞可渗透的，FKBP12依赖性激酶抑制剂的一般方法。这些抑制剂对RapaBlock的失活很敏感，可通过脑部抑制其各自的激酶靶标。