1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors.

Christopher Asquith,Panayiotis Koutentis,Rafael Couñago,Paulo Godoi,John Scott,David Drewry,Tuomo Laitinen,Jonathan Oakhill,Timothy Willson,Andreas Kalogirou,Christopher Langendorf,William Zuercher

doi:10.3390/molecules23051221

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.

Highlights

Protein kinases catalyze phosphate transfer from Adenosine Triphosphate (ATP) to tyrosine, Molecules 2018, 23, x threonine or serine residues in specific target proteins
The corresponding dianilino-TDZs (1–5) were synthesized in two-steps from 3,5-dichloro-4H-1,2,6-thiadiazin-4-one this strategy is that thethe firstfirst of the from
We proposed a series of modifications of compound 2 relating to the crystal structure and modelling (Figure 6)

Summary

Introduction

Protein kinases catalyze phosphate transfer from Adenosine Triphosphate (ATP) to tyrosine, Molecules 2018, 23, x threonine or serine residues in specific target proteins. These phosphorylation events occur in almost every pathway and and provide provide regulatory regulatory points points for for therapeutic therapeutic intervention intervention [1]. Kinases have been successfully utilized as drug targets for the past years, with kinase inhibitors. Kinases have been successfully utilized as drug targets for the past 30 years, with 38 kinase inhibitors approved approved by by the the FDA. Approval of kinase inhibitors for the treatment on inhibitors for the treatment of cancer [3].

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Conclusion