{"doi":"10.1101/2024.05.12.593776","title":"Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2","abstract":"ABSTRACT Acylaminoindazole-based inhibitors of CDKL2 were identified via analyses of cell-free binding and selectivity data. Compound 9 was selected as a CDKL2 chemical probe based on its potent inhibition of CDKL2 enzymatic activity, engagement of CDKL2 in cells, and excellent kinome-wide selectivity, especially when used in cells. Compound 16 was designed as a negative control to be used alongside compound 9 in experiments to interrogate CDKL2-mediated biology. A solved co-crystal structure of compound 9 bound to CDKL2 highlighted key interactions it makes within its ATP-binding site. Inhibition of downstream phosphorylation of EB2, a CDKL2 substrate, in rat primary neurons provided evidence that engagement of CDKL2 by compound 9 in cells resulted in inhibition of its activity. When used at relevant concentrations, compound 9 does not impact the viability of rat primary neurons or certain breast cancer cells nor elicit consistent changes in the expression of proteins involved in epithelial–mesenchymal transition.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":497607,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1009680,"name":"Sophia M. Min","orcid":"0000-0001-9840-2996","position":1,"is_corresponding":false},{"id":1107555,"name":"Xiangrong Chen","orcid":"0000-0003-0587-3444","position":2,"is_corresponding":false},{"id":497762,"name":"Stefanie Howell","orcid":"0000-0003-3392-2848","position":3,"is_corresponding":false},{"id":1309561,"name":"Caroline H. Rinderle","orcid":"0009-0001-2154-3907","position":4,"is_corresponding":false},{"id":1309562,"name":"Gabriel Morel","orcid":"0009-0003-3001-1886","position":5,"is_corresponding":false},{"id":485230,"name":"Josie A. Silvaroli","orcid":"0000-0002-4505-3670","position":6,"is_corresponding":false},{"id":273786,"name":"Carrow I. Wells","orcid":"0000-0003-4799-6792","position":7,"is_corresponding":false},{"id":282160,"name":"Bruce A. Bunnell","orcid":"0000-0001-6196-3722","position":8,"is_corresponding":false},{"id":273790,"name":"David H. Drewry","orcid":"0000-0001-5973-5798","position":9,"is_corresponding":false},{"id":310499,"name":"Navjotsingh Pabla","orcid":"0000-0001-9408-0539","position":10,"is_corresponding":false},{"id":1076940,"name":"Sila K. Ultanir","orcid":"0000-0001-5745-3957","position":11,"is_corresponding":false},{"id":369354,"name":"Alex N. Bullock","orcid":"0000-0001-6757-0436","position":12,"is_corresponding":false},{"id":376426,"name":"Alison D. Axtman","orcid":"0000-0003-4779-9932","position":13,"is_corresponding":false},{"id":1030943,"name":"Frances M. Bashore","orcid":"0000-0003-4241-9873","position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-19T02:09:34.764412Z","pmid":"38798634","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":[]}