Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2
2024
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
The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against &beta:-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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