{"doi":"10.1101/2025.07.03.663042","title":"LCK-targeting molecular glues overcome resistance to inhibitor-based therapy in T-cell acute lymphoblastic leukemia","abstract":"Drug resistance is a major challenge in cancer therapy, especially in the context of kinase inhibitors. While targeted protein degradation (TPD) was a distinct mode of action compared to inhibition-based therapeutic targeting, the potential value of TPD in drug-resistant cancer remains unclear. Here, we report the discovery of cereblon-recruiting molecular glue degraders (MGDs) targeting LCK, an oncogenic kinase in T-cell acute lymphoblastic leukemia (T-ALL). By high-throughput screening and medicinal chemistry optimization, we developed a series of MGDs that induced CRBN-dependent degradation of LCK as well as potent cytotoxicity in T-ALL in vitro. Structure-activity relationship analysis and ternary complex modeling revealed a non-canonical degron at the LCK-CRBN interface involving the G-loop, whose mutation disrupts this interaction. Unlike inhibitors and inhibitor-based PROTACs, these MGDs engage LCK in regions distal to the ATP binding site and thus their activities in T-ALL are not affected by gate-keeper LCK mutations that drive resistance to inhibitor-based therapeutics. Taken together, our data underscore the potential of LCK-targeting MGDs as a strategy to overcome kinase inhibitor resistance in T-ALL, highlighting a potentially generalizable strategy in cancer therapy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558439,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":627487,"name":"Gisele Nishiguchi","orcid":"0000-0003-2253-9325","position":1,"is_corresponding":false},{"id":328020,"name":"Satoshi Yoshimura","orcid":"0000-0002-4756-8790","position":2,"is_corresponding":false},{"id":629050,"name":"Marisa Actis","orcid":null,"position":3,"is_corresponding":false},{"id":309918,"name":"Justin T. Seffernick","orcid":null,"position":4,"is_corresponding":false},{"id":627484,"name":"Jamie Jarusiewicz","orcid":"0000-0003-4815-1505","position":5,"is_corresponding":false},{"id":580441,"name":"Anup Aggarwal","orcid":"0000-0003-1937-964X","position":6,"is_corresponding":false},{"id":1074228,"name":"Angelina Li","orcid":null,"position":7,"is_corresponding":false},{"id":627485,"name":"Yong Li","orcid":"0000-0001-9629-1137","position":8,"is_corresponding":false},{"id":891306,"name":"Dong Geun Lee","orcid":"0000-0003-3668-0485","position":9,"is_corresponding":false},{"id":345327,"name":"Lei Yang","orcid":"0000-0002-3060-0790","position":10,"is_corresponding":false},{"id":501998,"name":"Anand Mayasundari","orcid":null,"position":11,"is_corresponding":false},{"id":381383,"name":"Zoran Ranković","orcid":"0000-0001-6866-4290","position":12,"is_corresponding":false},{"id":627488,"name":"Marcus Fischer","orcid":"0000-0002-7179-2581","position":13,"is_corresponding":false},{"id":1459286,"name":"Jun J Yang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:55:25.969263Z","pmid":"40672235","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":[]}