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

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-<i>a</i>]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 <b>1</b>, we discovered compound <b>2</b> as a promising lead compound with improved in vivo metabolic stability. Compound <b>2</b> 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 <b>2</b> 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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Publication Details

Journal
Molecules
Published
2024-09-02
DOI
https://doi.org/10.3390/molecules29174158
Citations
2
Primary Topic
Protein Tyrosine Phosphatases
Type
article
Field-Weighted Citation Impact
0.47

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article

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

Marcia K. Sanders, Tammy M. Havener, Mark T. Heise, Alison Donnelly Axtman et al.
2 citations
Molecules
Protein Tyrosine Phosphatases
0.47
article

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

Marcia K. Sanders, Tammy M. Havener, Mark T. Heise, Alison Donnelly Axtman, Han Wee Ong, Rebekah J. Dickmander, Xuan Yang, Nathaniel J. Moorman, Jason W. Brown, Rafael M. Couñago, Sharon Taft-Benz, Edcon Chang, David H. Drewry, Stefanie Howell, Timothy M. Willson, Jeffery L. Smith, Andreas Krämer
article en
2 citations

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-<i>a</i>]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 <b>1</b>, we discovered compound <b>2</b> as a promising lead compound with improved in vivo metabolic stability. Compound <b>2</b> 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 <b>2</b> 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.

MoleculesVol. 29(17)
University of North Carolina at Chapel Hill (US), Goethe University Frankfurt (DE), Universidade Estadual de Campinas (UNICAMP) (BR), Takeda (United States) (US)
Pfizer, Bayer, Merck KGaA
Good health and well-being
Openalex Percentile: Top 35%
Protein Tyrosine Phosphatases
0.47
DOIOpen Access PDFOpenAlex
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