{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Ong HW"],"funding":["NIH Illuminating the Druggable Genome","University of North Carolina","NIDDK NIH HHS","Takeda Pharmaceutical Company","U.S. Department of Defense","National Institutes of Health","North Carolina Biotechnology Center","NIH HHS","North Carolina General Assembly"],"pagination":["12261-12313"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11284802"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["67(14)"],"pubmed_abstract":["The pyrazolo[1,5-<i>a</i>]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-<i>a</i>]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor <b>53</b>. Despite excellent in vitro metabolic stabilit"],"journal":["Journal of medicinal chemistry"],"pubmed_title":["More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-&lt;i&gt;a&lt;/i&gt;]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication."],"pmcid":["PMC11284802"],"funding_grant_id":["S10 OD032476","AL190107","1U24DK116204-01","S10OD032476","U24 DK116204","2018-IDG-1030"],"pubmed_authors":["Capener JL","Havener TM","Brown JW","Drewry DH","Ong HW","Willson TM","Dickmander RJ","Axtman AD","Yang X","Taft-Benz S","Howell S","Moorman NJ","Kramer A","Smith JL","Counago RM","Chang E","Heise M","Sanders MK"],"additional_accession":[]},"is_claimable":false,"name":"More than an Amide Bioisostere: Discovery of 1,2,4-Triazole-containing Pyrazolo[1,5-&lt;i&gt;a&lt;/i&gt;]pyrimidine Host CSNK2 Inhibitors for Combatting β-Coronavirus Replication.","description":"The pyrazolo[1,5-<i>a</i>]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5-<i>a</i>]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor <b>53</b>. Despite excellent in vitro metabolic stabilit","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Jul","modification":"2026-06-01T13:27:31.291Z","creation":"2026-04-08T13:07:16.2Z"},"accession":"S-EPMC11284802","cross_references":{"pubmed":["38959455"],"doi":["10.1021/acs.jmedchem.4c00962"]}}