Preparation and evaluation of deconstruction analogues of 7-deoxykalafungin as AKT kinase inhibitors |
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| Institution: | 1. Department of Paraclinical Sciences, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa;2. Department of Production Animal Studies, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa;3. Biomedical Research Centre, Faculty of Veterinary Science, University of Pretoria, Pretoria, South Africa;1. ‘Alexandru Ioan Cuza’ University of Iasi, Faculty of Chemistry, Bd. Carol I nr. 11, 700506 Iasi, Romania;2. Univ. Lille, Faculté des Sciences Pharmaceutiques et Biologiques, Rue du Pr Laguesse, B.P. 83, F-59006 Lille, France;3. Institut de Chimie des Substances Naturelles, UPR2301 CNRS, Centre de Recherche de Gif, Avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France;4. Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, F-59000 Lille, France;5. Yncréa Hauts-de-France, Hautes Etudes d’Ingénieur (HEI), UCLille, Health & Environment Department, Sustainable Chemistry Team, Laboratoire de Chimie Durable et Santé, 13 rue de Toul, F-59046 Lille, France |
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| Abstract: | The pyranonaphthoquinone (PNQ) lactone natural products, including 7-deoxykalafungin, have been reported to be potent and selective covalent inhibitors of AKT kinase. In this work we seek to identify structural features of the natural product scaffold that are essential for potency and selectivity. Using a deconstruction approach, we designed and prepared simplified analogues of 7-deoxykalafungin. Testing of the compounds for their ability to inhibit AKT and the closely related kinase PKA revealed that the 3,6-dihydro-2H-pyran ring of the PNQ lactones is required for potent and selective inhibition of AKT. We have also unexpectedly identified a new submicromolar inhibitor of PKA. |
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| Keywords: | Pyranonaphthoquinone lactone Covalent inhibitor AKT kinase Deconstruction analogues 7-Deoxykalafungin |
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