Strategic Fluorination to Achieve a Potent, Selective, Metabolically Stable, and Orally Bioavailable Inhibitor of CSNK2
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
Affiliations
Han Wee Ong
Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA
Xuan Yang
Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA
Jeffery L. Smith
Structural Genomics Consortium (SGC) and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Sharon Taft-Benz
Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA
Stefanie Howell
Structural Genomics Consortium (SGC) and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Rebekah J. Dickmander
Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA
Tammy M. Havener
Structural Genomics Consortium (SGC) and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Marcia K. Sanders
Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA
Jason W. Brown
Takeda Development Center Americas, Inc., San Diego, CA 92121, USA
Rafael M. Couñago
Structural Genomics Consortium (SGC) and Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Edcon Chang
Takeda Development Center Americas, Inc., San Diego, CA 92121, USA
Andreas Krämer
Structural Genomics Consortium (SGC), Institute of Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany
Nathaniel J. Moorman
Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA
Mark Heise
Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA
Alison D. Axtman
Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA
David H. Drewry
Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA
Timothy M. Willson
Rapidly Emerging Antiviral Drug Development Initiative (READDI), Chapel Hill, NC 27599, USA
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.
