Literature

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.

DOI： 10.1016/j.bmcl.2013.11.020

Preparation and evaluation of deconstruction analogues of 7-deoxykalafungin as AKT kinase inhibitors

Bioorganic & Medicinal Chemistry Letters 2014.0

Pyranonaphthoquinone Lactones: A New Class of AKT Selective Kinase Inhibitors Alkylate a Regulatory Loop Cysteine

Journal of Medicinal Chemistry 2009.0

Identification of a novel 3,5-disubstituted pyridine as a potent, selective, and orally active inhibitor of Akt1 kinase

Bioorganic & Medicinal Chemistry Letters 2006.0

Discovery and SAR of oxindole–pyridine-based protein kinase B/Akt inhibitors for treating cancers

Bioorganic & Medicinal Chemistry Letters 2006.0

Synthesis and structure–activity relationship of 3,4′-bispyridinylethylenes: Discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer

Bioorganic & Medicinal Chemistry Letters 2006.0

Discovery of trans-3,4′-bispyridinylethylenes as potent and novel inhibitors of protein kinase B (PKB/Akt) for the treatment of cancer: Synthesis and biological evaluation