{"doi":"10.3390/molecules29174158","title":"Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2","abstract":"The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug target in vivo, potent and selective CSNK2 inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold possess outstanding potency and selectivity for CSNK2, but bioavailability and metabolic stability are often challenging. By strategically installing a fluorine atom on an electron-rich phenyl ring of a previously characterized inhibitor 1, we discovered compound 2 as a promising lead compound with improved in vivo metabolic stability. Compound 2 maintained excellent cellular potency against CSNK2, submicromolar antiviral potency, and favorable solubility, and was remarkably selective for CSNK2 when screened against 192 kinases across the human kinome. We additionally present a co-crystal structure to support its on-target binding mode. In vivo, compound 2 was orally bioavailable, and demonstrated modest and transient inhibition of CSNK2, although antiviral activity was not observed, possibly attributed to its lack of prolonged CSNK2 inhibition.","journal":"Molecules","year":2024,"id":471782,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"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":694934,"name":"Xuan Yang","orcid":"0000-0001-6818-158X","position":1,"is_corresponding":false},{"id":891302,"name":"Jeffery L. Smith","orcid":"0000-0003-2189-0420","position":2,"is_corresponding":false},{"id":333823,"name":"Sharon Taft-Benz","orcid":"0000-0002-0965-8760","position":3,"is_corresponding":false},{"id":497762,"name":"Stefanie Howell","orcid":"0000-0003-3392-2848","position":4,"is_corresponding":false},{"id":891300,"name":"Rebekah J. Dickmander","orcid":"0000-0002-5367-6587","position":5,"is_corresponding":false},{"id":461234,"name":"Tammy M. Havener","orcid":"0000-0002-4613-0498","position":6,"is_corresponding":false},{"id":548678,"name":"Marcia K. Sanders","orcid":"0000-0002-0931-7560","position":7,"is_corresponding":false},{"id":280749,"name":"Joshua B. Brown","orcid":"0000-0002-6936-035X","position":8,"is_corresponding":false},{"id":471230,"name":"Rafael M. Couñago","orcid":"0000-0003-1847-5090","position":9,"is_corresponding":false},{"id":891303,"name":"Edcon Chang","orcid":"0000-0001-9534-0291","position":10,"is_corresponding":false},{"id":634299,"name":"Andreas Krämer","orcid":"0000-0003-3294-2660","position":11,"is_corresponding":false},{"id":392102,"name":"Nathaniel J. Moorman","orcid":"0000-0003-4952-6858","position":12,"is_corresponding":false},{"id":275061,"name":"Mark T. Heise","orcid":"0000-0001-5829-8477","position":13,"is_corresponding":false},{"id":376426,"name":"Alison D. Axtman","orcid":"0000-0003-4779-9932","position":14,"is_corresponding":false},{"id":273790,"name":"David H. Drewry","orcid":"0000-0001-5973-5798","position":15,"is_corresponding":false},{"id":273796,"name":"Timothy M. Willson","orcid":"0000-0003-4181-8223","position":16,"is_corresponding":false},{"id":912100,"name":"Han Wee Ong","orcid":"0000-0003-3232-2373","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T02:05:48.788780Z","pmid":"39275006","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":[]}