{"doi":"10.1101/2023.10.23.563687","title":"Borrowing Transcriptional Kinases to Activate Apoptosis","abstract":"Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. Here chemically induced proximity is leveraged to convert kinase inhibitors into context-specific activators of therapeutic genes. Bivalent molecules that link ligands of the transcription factor B-cell lymphoma 6 (BCL6) to ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) were developed to re-localize CDK to BCL6-bound loci on chromatin and direct phosphorylation of RNA Pol II. The resulting BCL6-target proapoptotic gene expression translated into killing of diffuse large B-cell lymphoma (DLBCL) cells at 72 h with EC50s of 0.9 - 10 nM and highly specific ablation of the BCL6-regulated germinal center response in mice. The molecules exhibited 10,000-fold lower cytotoxicity in normal lymphocytes and are well tolerated in mice. Genomic and proteomic evidence corroborated a gain-of-function mechanism where, instead of global enzyme inhibition, a fraction of total kinase activity is borrowed and re-localized to BCL6-bound loci. The strategy demonstrates how kinase inhibitors can be used to context-specifically activate transcription, accessing new therapeutic space.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":393766,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":986376,"name":"Sai Gourisankar","orcid":"0000-0003-0132-8086","position":1,"is_corresponding":false},{"id":1167863,"name":"Basel A. Karim","orcid":"0000-0002-7928-0433","position":2,"is_corresponding":false},{"id":290774,"name":"Sabin A. Nettles","orcid":"0000-0002-1913-9016","position":3,"is_corresponding":false},{"id":255857,"name":"Haopeng Yang","orcid":"0000-0002-3870-2679","position":4,"is_corresponding":false},{"id":577164,"name":"Brendan G. Dwyer","orcid":"0000-0001-8593-4184","position":5,"is_corresponding":false},{"id":986378,"name":"Juste Simanauskaite","orcid":"0009-0009-1385-2599","position":6,"is_corresponding":false},{"id":1031974,"name":"Jason Tse","orcid":"0000-0002-6958-0256","position":7,"is_corresponding":false},{"id":1063882,"name":"Hind Abuzaid","orcid":"0000-0002-5454-7672","position":8,"is_corresponding":false},{"id":46794,"name":"A. Krokhotin","orcid":"0009-0006-4435-3213","position":9,"is_corresponding":false},{"id":226576,"name":"Tinghu Zhang","orcid":"0000-0003-1028-8020","position":10,"is_corresponding":false},{"id":782455,"name":"Stephen M. Hinshaw","orcid":"0000-0003-4215-5206","position":11,"is_corresponding":false},{"id":17225,"name":"Michael R. Green","orcid":"0000-0001-6309-9472","position":12,"is_corresponding":false},{"id":325781,"name":"Gerald R. Crabtree","orcid":"0000-0001-9685-7911","position":13,"is_corresponding":false},{"id":226581,"name":"Nathanael S. Gray","orcid":"0000-0001-5354-7403","position":14,"is_corresponding":false},{"id":557485,"name":"Roman C. Sarott","orcid":"0000-0001-8789-6150","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:05.913428Z","pmid":"37961702","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":[]}