title: Preparation and evaluation of deconstruction analogues of 7-deoxykalafungin as AKT kinase inhibitors.
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.
authors: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Biotech 1, 800 East Leigh Street, Richmond, VA 23298, USA.
authors: Sudha
authors: S
authors: Korwar
authors: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Biotech 1, 800 East Leigh Street, Richmond, VA 23298, USA.
authors: Thuy
authors: T
authors: Nguyen
authors: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Biotech 1, 800 East Leigh Street, Richmond, VA 23298, USA. Electronic address: kcellis@vcu.edu.
authors: Keith C
authors: KC
authors: Ellis
mesh_terms: D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C534897:7-deoxykalafungin; D009285:Naphthoquinones; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt
keywords: 7-Deoxykalafungin; AKT kinase; Covalent inhibitor; Deconstruction analogues; Pyranonaphthoquinone lactone