Article Metrics


Online attention

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

DOI: 10.3390/molecules23051221 DOI Help

Authors: Christopher Asquith (Structural Genomics Consortium, University of North Carolina at Chapel Hill) , Paulo Godoi (Structural Genomics Consortium) , Rafael M. Counago (Structural Genomics Consortium; Center for Molecular and Genetic Engineering (CBMEG), University of Campinas (UNICAMP)) , Tuomo Laitinen (University of Eastern Finland) , John W. Scott (University of Melbourne; Australian Catholic University; The Florey Institute of Neuroscience and Mental Health) , Christopher Langendorf (University of Melbourne) , Jonathan S. Oakhill (University of Melbourne; Australian Catholic University) , David Drewry (Structural Genomics Consortium) , William Zuercher (Structural Genomics Consortium, University of North Carolina at Chapel Hill) , Panayiotis Koutentis (University of Cyprus) , Timothy Willson (Structural Genomics Consortium, University of North Carolina at Chapel Hill) , Andreas Kalogirou (University of Cyprus; European University Cyprus)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecules , VOL 23

State: Published (Approved)
Published: May 2018
Diamond Proposal Number(s): 14664

Open Access Open Access

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.

Journal Keywords: thiadiazinone; hinge binder; kinase inhibitor design; kinase water network; CaMKK2

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 24/05/2018 14:57

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)