In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds

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 indi...

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Main Authors:	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
Format:	Article
Language:	English
Published:	MDPI AG 2020-01-01
Series:	Molecules
Subjects:	kinase camkk2 sto-609 chemical probes oncology kinase inhibitors
Online Access:	https://www.mdpi.com/1420-3049/25/2/325

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spelling	doaj-d806b3ec018a4bf9b9a5cb50cf8208cc2020-11-25T01:45:08ZengMDPI AGMolecules1420-30492020-01-0125232510.3390/molecules25020325molecules25020325In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory ScaffoldsSean N. O’Byrne0John W. Scott1Joseph R. Pilotte2André da S. Santiago3Christopher G. Langendorf4Jonathan S. Oakhill5Benjamin J. Eduful6Rafael M. Couñago7Carrow I. Wells8William J. Zuercher9Timothy M. Willson10David H. Drewry11Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USASt Vincent’s Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, AustraliaStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USACentro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas SP 13083-875, BrazilSt Vincent’s Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, AustraliaSt Vincent’s Institute and Department of Medicine, The University of Melbourne, 41 Victoria Parade, Fitzroy 3065, AustraliaStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USACentro de Química Medicinal (CQMED), Centro de Biologia Molecular e Engenharia Genética (CBMEG), Universidade Estadual de Campinas (UNICAMP), Campinas SP 13083-875, BrazilStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAStructural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAThe 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.https://www.mdpi.com/1420-3049/25/2/325kinasecamkk2sto-609chemical probesoncologykinase inhibitors
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	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
spellingShingle	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 In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds Molecules kinase camkk2 sto-609 chemical probes oncology kinase inhibitors
author_facet	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
author_sort	Sean N. O’Byrne
title	In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds
title_short	In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds
title_full	In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds
title_fullStr	In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds
title_full_unstemmed	In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds
title_sort	in depth analysis of kinase cross screening data to identify camkk2 inhibitory scaffolds
publisher	MDPI AG
series	Molecules
issn	1420-3049
publishDate	2020-01-01
description	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.
topic	kinase camkk2 sto-609 chemical probes oncology kinase inhibitors
url	https://www.mdpi.com/1420-3049/25/2/325
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In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds

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