Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2.

Publication date: Sep 02, 2024

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.

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Concepts Keywords
Antiviral Administration, Oral
Bioavailability Animals
Kinase antiviral
Pyrazolo15 Antiviral Agents
Rich Antiviral Agents
Biological Availability
Casein Kinase II
Casein Kinase II
CSNK2
fluorination
Halogenation
Humans
Protein Kinase Inhibitors
Protein Kinase Inhibitors
pyrazolo[1,5-a]pyrimidine
Pyrimidines
Pyrimidines
SARS-CoV-2
SARS-CoV-2
Structure-Activity Relationship
β-coronavirus

Semantics

Type Source Name
disease IDO host
disease MESH infection
drug DRUGBANK Coenzyme M
disease MESH emergency
drug DRUGBANK Ritonavir
disease MESH tic
disease IDO replication
pathway REACTOME Metabolism
drug DRUGBANK Glutathione
pathway KEGG Metabolic pathways
pathway KEGG Viral replication
drug DRUGBANK Aniline
disease IDO assay
disease MESH hepatitis
drug DRUGBANK Phosphate ion
drug DRUGBANK Dimethyl sulfoxide
drug DRUGBANK Water

Original Article

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