Design and synthesis of Coenzyme A analogues as Aurora kinase A inhibitors: An exploration of the roles of the pyrophosphate and pantetheine moieties.

Autor: Bellany F; Department of Chemistry, UCL, Christopher Ingold Building, 20, Gordon Street, London WC1H 0AJ, UK., Tsuchiya Y; Department of Structural and Molecular Biology, UCL, Gower Street, London WC1E 6BT, UK., Tran TM; Department of Chemistry, UCL, Christopher Ingold Building, 20, Gordon Street, London WC1H 0AJ, UK., Chan AWE; Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK., Allan H; Department of Chemistry, UCL, Christopher Ingold Building, 20, Gordon Street, London WC1H 0AJ, UK., Gout I; Department of Structural and Molecular Biology, UCL, Gower Street, London WC1E 6BT, UK., Tabor AB; Department of Chemistry, UCL, Christopher Ingold Building, 20, Gordon Street, London WC1H 0AJ, UK. Electronic address: a.b.tabor@ucl.ac.uk.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2020 Nov 15; Vol. 28 (22), pp. 115740. Date of Electronic Publication: 2020 Sep 05.
DOI: 10.1016/j.bmc.2020.115740
Abstrakt: Coenzyme A (CoA) is a highly selective inhibitor of the mitotic regulatory enzyme Aurora A kinase, with a novel mode of action. Herein we report the design and synthesis of analogues of CoA as inhibitors of Aurora A kinase. We have designed and synthesised modified CoA structures as potential inhibitors, combining dicarbonyl mimics of the pyrophosphate group with a conserved adenosine headgroup and different length pantetheine-based tail groups. An analogue with a -SH group at the end of the pantotheinate tail showed the best IC50, probably due to the formation of a covalent bond with Aurora A kinase Cys290.
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Databáze: MEDLINE
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