1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Inhibitors

Christopher R.M. Asquith; Paulo H. Godoi; Rafael M. Couñago; Tuomo Laitinen; John W. Scott; Christopher G. Langendorf; Jonathan S. Oakhill; David H. Drewry; William J. Zuercher; Panayiotis A. Koutentis; Timothy M. Willson; Andreas S. Kalogirou

doi:10.3390/molecules23051221

1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Inhibitors

Christopher R.M. Asquith, Paulo H. Godoi, Rafael M. Couñago, Tuomo Laitinen, John W. Scott, Christopher G. Langendorf, Jonathan S. Oakhill, David H. Drewry, William J. Zuercher, Panayiotis A. Koutentis, Timothy M. Willson, Andreas S. Kalogirou

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24 Citations (Scopus)

Abstract

We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors.

Original language	English
Article number	1221
Number of pages	23
Journal	Molecules
Volume	23
Issue number	5
DOIs	https://doi.org/10.3390/molecules23051221
Publication status	Published - 2018
Externally published	Yes

Keywords

CaMKK2
Hinge binder
Kinase inhibitor design
Kinase water network
Thiadiazinone

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10.3390/molecules23051221Licence: CC BY

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Asquith, C. R. M., Godoi, P. H., Couñago, R. M., Laitinen, T., Scott, J. W., Langendorf, C. G., Oakhill, J. S., Drewry, D. H., Zuercher, W. J., Koutentis, P. A., Willson, T. M., & Kalogirou, A. S. (2018). 1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Inhibitors. Molecules, 23(5), Article 1221. https://doi.org/10.3390/molecules23051221

@article{a9520f6b2fe34338b7fd201676c53b4f,

title = "1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Inhibitors",

abstract = "We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors.",

keywords = "CaMKK2, Hinge binder, Kinase inhibitor design, Kinase water network, Thiadiazinone",

author = "Asquith, {Christopher R.M.} and Godoi, {Paulo H.} and Cou{\~n}ago, {Rafael M.} and Tuomo Laitinen and Scott, {John W.} and Langendorf, {Christopher G.} and Oakhill, {Jonathan S.} and Drewry, {David H.} and Zuercher, {William J.} and Koutentis, {Panayiotis A.} and Willson, {Timothy M.} and Kalogirou, {Andreas S.}",

note = "Funding Information: Funding: This research was funded by the University of Cyprus grant number [postdoctoral funding (A.S.K.)]; the Cyprus Research Promotion Foundation grant number [NEAYPODOMH/NEKYP/0308/02)], the National Cancer Institute of the National Institute of Health grant number [R01CA218442]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health. Funding Information: Acknowledgments: The authors thank the University of Cyprus, the Cyprus Research Promotion Foundation, the National Cancer Institute of the National Institute of Health and the following organizations and companies in Cyprus for generous donations of chemicals and glassware: The State General Laboratory; the Agricultural Research Institute; the Ministry of Agriculture; MedoChemie, Ltd.; Medisell, Ltd.; and Biotronics, Ltd. Furthermore, we thank the A. G. Leventis Foundation for helping to establish the NMR facility at the University of Cyprus. In addition, we thank Brandie M. Ehrmann for LC-MS/HRMS support provided by the Mass Spectrometry Core Laboratory at the University of North Carolina at Chapel Hill, and thank Yi Liang and Opher Gileadi for support and assistance. We also thank the Biocenter Finland/DDCB for financial support towards the goals of our work and the CSC-IT Center for Science Ltd. (Finland) for the allocation of computational resources. We thank Diamond Light Source for access to beamline I03 (MX14664) that contributed to the results presented here. Funding Information: We also acknowledge-The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA), Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, S{\~a}o Paulo Research Foundation-FAPESP, Takeda and Wellcome Trust. Funding Information: The authors thank the University of Cyprus, the Cyprus Research Promotion Foundation, the National Cancer Institute of the National Institute of Health and the following organizations and companies in Cyprus for generous donations of chemicals and glassware: The State General Laboratory; the Agricultural Research Institute; the Ministry of Agriculture; MedoChemie, Ltd.; Medisell, Ltd.; and Biotronics, Ltd. Furthermore, we thank the A. G. Leventis Foundation for helping to establish the NMR facility at the University of Cyprus. In addition, we thank Brandie M. Ehrmann for LC-MS/HRMS support provided by the Mass Spectrometry Core Laboratory at the University of North Carolina at Chapel Hill, and thank Yi Liang and Opher Gileadi for support and assistance. We also thank the Biocenter Finland/DDCB for financial support towards the goals of our work and the CSC-IT Center for Science Ltd. (Finland) for the allocation of computational resources. We thank Diamond Light Source for access to beamline I03 (MX14664) that contributed to the results presented here. Publisher Copyright: {\textcopyright} 2018 by the authors.",

year = "2018",

doi = "10.3390/molecules23051221",

language = "English",

volume = "23",

journal = "Molecules",

issn = "1420-3049",

publisher = "MDPI AG",

number = "5",

}

TY - JOUR

T1 - 1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Inhibitors

AU - Asquith, Christopher R.M.

AU - Godoi, Paulo H.

AU - Couñago, Rafael M.

AU - Laitinen, Tuomo

AU - Scott, John W.

AU - Langendorf, Christopher G.

AU - Oakhill, Jonathan S.

AU - Drewry, David H.

AU - Zuercher, William J.

AU - Koutentis, Panayiotis A.

AU - Willson, Timothy M.

AU - Kalogirou, Andreas S.

N1 - Funding Information: Funding: This research was funded by the University of Cyprus grant number [postdoctoral funding (A.S.K.)]; the Cyprus Research Promotion Foundation grant number [NEAYPODOMH/NEKYP/0308/02)], the National Cancer Institute of the National Institute of Health grant number [R01CA218442]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health. Funding Information: Acknowledgments: The authors thank the University of Cyprus, the Cyprus Research Promotion Foundation, the National Cancer Institute of the National Institute of Health and the following organizations and companies in Cyprus for generous donations of chemicals and glassware: The State General Laboratory; the Agricultural Research Institute; the Ministry of Agriculture; MedoChemie, Ltd.; Medisell, Ltd.; and Biotronics, Ltd. Furthermore, we thank the A. G. Leventis Foundation for helping to establish the NMR facility at the University of Cyprus. In addition, we thank Brandie M. Ehrmann for LC-MS/HRMS support provided by the Mass Spectrometry Core Laboratory at the University of North Carolina at Chapel Hill, and thank Yi Liang and Opher Gileadi for support and assistance. We also thank the Biocenter Finland/DDCB for financial support towards the goals of our work and the CSC-IT Center for Science Ltd. (Finland) for the allocation of computational resources. We thank Diamond Light Source for access to beamline I03 (MX14664) that contributed to the results presented here. Funding Information: We also acknowledge-The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA), Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda and Wellcome Trust. Funding Information: The authors thank the University of Cyprus, the Cyprus Research Promotion Foundation, the National Cancer Institute of the National Institute of Health and the following organizations and companies in Cyprus for generous donations of chemicals and glassware: The State General Laboratory; the Agricultural Research Institute; the Ministry of Agriculture; MedoChemie, Ltd.; Medisell, Ltd.; and Biotronics, Ltd. Furthermore, we thank the A. G. Leventis Foundation for helping to establish the NMR facility at the University of Cyprus. In addition, we thank Brandie M. Ehrmann for LC-MS/HRMS support provided by the Mass Spectrometry Core Laboratory at the University of North Carolina at Chapel Hill, and thank Yi Liang and Opher Gileadi for support and assistance. We also thank the Biocenter Finland/DDCB for financial support towards the goals of our work and the CSC-IT Center for Science Ltd. (Finland) for the allocation of computational resources. We thank Diamond Light Source for access to beamline I03 (MX14664) that contributed to the results presented here. Publisher Copyright: © 2018 by the authors.

PY - 2018

Y1 - 2018

N2 - We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors.

AB - We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors.

KW - CaMKK2

KW - Hinge binder

KW - Kinase inhibitor design

KW - Kinase water network

KW - Thiadiazinone

UR - http://www.scopus.com/inward/record.url?scp=85047477636&partnerID=8YFLogxK

U2 - 10.3390/molecules23051221

DO - 10.3390/molecules23051221

M3 - Article

C2 - 29783765

AN - SCOPUS:85047477636

SN - 1420-3049

VL - 23

JO - Molecules

JF - Molecules

IS - 5

M1 - 1221

ER -

1,2,6-thiadiazinones as novel narrow spectrum calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) Inhibitors

Abstract

Keywords

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