In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds
Sean N. O’Byrne,
John W. Scott,
Joseph R. Pilotte,
André da S. Santiago,
Christopher G. Langendorf,
Jonathan S. Oakhill,
Benjamin J. Eduful,
Rafael M. Couñago,
Carrow I. Wells,
William J. Zuercher,
Timothy M. Willson,
David H. Drewry
Affiliations
Sean N. O’Byrne
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
John W. Scott
St Vincent’s Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia
Joseph R. Pilotte
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
André da S. Santiago
Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas SP 13083-875, Brazil
Christopher G. Langendorf
St Vincent’s Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia
Jonathan S. Oakhill
St Vincent’s Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia
Benjamin J. Eduful
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Rafael M. Couñago
Centro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas SP 13083-875, Brazil
Carrow I. Wells
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
William J. Zuercher
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Timothy M. Willson
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
David H. Drewry
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
The calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) activates CAMK1, CAMK4, AMPK, and AKT, leading to numerous physiological responses. The deregulation of CAMKK2 is linked to several diseases, suggesting the utility of CAMKK2 inhibitors for oncological, metabolic and inflammatory indications. In this work, we demonstrate that STO-609, frequently described as a selective inhibitor for CAMKK2, potently inhibits a significant number of other kinases. Through an analysis of literature and public databases, we have identified other potent CAMKK2 inhibitors and verified their activities in differential scanning fluorimetry and enzyme inhibition assays. These inhibitors are potential starting points for the development of selective CAMKK2 inhibitors and will lead to tools that delineate the roles of this kinase in disease biology.
