Authors
Han Wee Ong, Xuan Yang, Jeffery L Smith, Sharon Taft-Benz, Stefanie Howell, Rebekah J Dickmander, Tammy M Havener, Marcia K Sanders, Jason W Brown, Rafael M Couñago, Edcon Chang, Andreas Krämer, Nathaniel J Moorman, Mark Heise, Alison D Axtman, David H Drewry, Timothy M Willson
Published in
Molecules (Basel, Switzerland). Volume 29. Issue 17. Sep 02, 2024. Epub Sep 02, 2024.
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.
PMID:
39275006
Bibliographic data and abstract were imported from PubMed on 14 Sep 2024.
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