{"doi":"10.37349/etat.2020.00017","title":"PROTACs are effective in addressing the platelet toxicity associated with BCL-XL inhibitors","abstract":"BCL-XL is an anti-apoptotic protein that plays an important role in tumorigenesis, metastasis, and intrinsic or therapy-induced cancer drug resistance. More recently, BCL-XL has also been identified as a key survival factor in senescent cells. Accumulation of senescent cells has been indicated as a causal factor of aging and many age-related diseases and contributes to tumor relapse and metastasis. Thus, inhibition of BCL-XL is an attractive strategy for the treatment of cancer and extension of healthspan. However, development of BCL-XL inhibitors such as navitoclax for clinical use has been challenging because human platelets depend on BCL-XL for survival. In this review, we discuss how BCL-XL-targeted proteolysis targeting chimeras (PROTACs) afford a novel approach to mitigate the on-target thrombocytopenia associated with BCL-XL inhibition. We summarize the progress in the development of BCL-XL PROTACs. We highlight the in vitro and in vivo data supporting that by hijacking the ubiquitin protein ligase (E3) that are poorly expressed in human platelets, BCL-XL PROTACs can significantly improve the therapeutic window compared to conventional BCL-XL inhibitors. These findings demonstrated the potentially broad utility of PROTAC technology to achieve tissue selectivity through recruiting differentially expressed E3 ligases and to reduce on-target toxicity.","journal":"Exploration of Targeted Anti-tumor Therapy","year":2020,"id":105653,"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":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"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":237864,"name":"Xuan Zhang","orcid":"0000-0001-6062-6708","position":1,"is_corresponding":false},{"id":237870,"name":"Xingui Liu","orcid":"0000-0003-2659-8007","position":2,"is_corresponding":false},{"id":237869,"name":"Sajid Khan","orcid":"0000-0003-1331-8846","position":3,"is_corresponding":false},{"id":237881,"name":"Daohong Zhou","orcid":"0000-0002-2400-6461","position":4,"is_corresponding":false},{"id":237880,"name":"Guangrong Zheng","orcid":"0000-0002-8106-6663","position":5,"is_corresponding":false},{"id":237867,"name":"Peiyi Zhang","orcid":"0000-0003-0207-1112","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-18T23:12:21.275494Z","pmid":"34296214","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":[]}