{"doi":"10.1101/2020.10.12.336677","title":"Brain-Restricted mTOR Inhibition with Binary Pharmacology","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":120551,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":558480,"name":"Qi-Wen Fan","orcid":null,"position":1,"is_corresponding":false},{"id":557979,"name":"Xujun Luo","orcid":"0000-0002-8924-4217","position":2,"is_corresponding":false},{"id":103654,"name":"Kevin Lou","orcid":"0000-0003-4939-4381","position":3,"is_corresponding":false},{"id":351797,"name":"William A. Weiss","orcid":"0000-0003-2230-9132","position":4,"is_corresponding":false},{"id":1361,"name":"Kevan M. Shokat","orcid":"0000-0001-8590-7741","position":5,"is_corresponding":false},{"id":103649,"name":"Ziyang Zhang","orcid":"0000-0003-0541-7211","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-18T23:14:33.640077Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}