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New Paper – Irreversible Inhibitors of Nek2 Kinase
2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase
RSC Med. Chem., 2020, 11, 707-731
https://pubs.rsc.org/en/content/articlelanding/2020/...
https://doi.org/10.1039/D0MD00074D
Christopher J. Matheson, Christopher R. Coxon, Richard Bayliss, Kathy Boxall Benoit Carbain, Andrew M. Fry, Ian R. Hardcastle, Suzannah J. Harnor, Corine Mas-Droux, David R. Newell, Mark W. Richards, Mangaleswaran Sivaprakasam, David Turner, Roger J. Griffin, Bernard T. Golding, Céline Cano*
Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. Primarily the work of Chris Matheson and Chris Coxon, this work reports the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase.
Examination of the crystal structure of non-covalent inhibitor 3-((6- cyclohexylmethoxy-7H-purin-2-yl)amino)benzamide 1 in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition.
A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the N-phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. X-ray crystallographic analysis confirmed that binding to the Nek2 ATP-binding site resulted in covalent modification of Cys22.
It is concluded that selective covalent binding to Nek2 can be achieved with 6-ethynylpurines.
Last modified: Mon, 19 Dec 2022 17:32:24 GMT
