{"doi":"10.1101/2023.12.28.573261","title":"Discovery and Optimization of Narrow Spectrum Inhibitors of Tousled Like Kinase 2 (TLK2) Using Quantitative Structure Activity Relationships","abstract":"The oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was a potent off-target kinase. The oxindole has long been considered a promiscuous inhibitor template, but across these 4 specific literature oxindoles TLK2 activity was consistent, while the kinome profile was radically different from narrow to broad spectrum coverage. We synthesized a large series of analogues and through quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites, small-molecule x-ray structural analysis and kinome profiling, narrow spectrum, sub-family selective, chemical tool compounds were identified to enable elucidation of TLK2 biology.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":402081,"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":0.9496,"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":373284,"name":"Michael P. East","orcid":"0000-0002-1994-6117","position":1,"is_corresponding":false},{"id":785119,"name":"Tuomo Laitinen","orcid":"0000-0003-1539-2142","position":2,"is_corresponding":false},{"id":1126181,"name":"Carla Alamillo‐Ferrer","orcid":"0000-0003-3607-846X","position":3,"is_corresponding":false},{"id":1179765,"name":"Erkka Hartikainen","orcid":null,"position":4,"is_corresponding":false},{"id":273786,"name":"Carrow I. Wells","orcid":"0000-0003-4799-6792","position":5,"is_corresponding":false},{"id":376426,"name":"Alison D. Axtman","orcid":"0000-0003-4779-9932","position":6,"is_corresponding":false},{"id":273790,"name":"David H. Drewry","orcid":"0000-0001-5973-5798","position":7,"is_corresponding":false},{"id":1179468,"name":"Graham J. Tizzard","orcid":"0000-0002-1577-5779","position":8,"is_corresponding":false},{"id":723587,"name":"Antti Poso","orcid":"0000-0003-4196-4204","position":9,"is_corresponding":false},{"id":273796,"name":"Timothy M. Willson","orcid":"0000-0003-4181-8223","position":10,"is_corresponding":false},{"id":2220,"name":"Gary L. Johnson","orcid":"0000-0003-2867-0551","position":11,"is_corresponding":false},{"id":578571,"name":"Christopher R. M. Asquith","orcid":"0000-0001-5871-3458","position":0,"is_corresponding":true}],"reference_count":94,"raw_metadata":null,"created_at":"2026-07-19T01:20:23.920156Z","pmid":"38234837","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":[]}