Discovery of a Novel Pseudo-Natural Product Aurora Kinase Inhibitor Chemotype through Morphological Profiling

The pseudo-natural product (pseudo-NP) concept aims to combine NP fragments in arrangements that are not accessible through known biosynthetic pathways. The resulting compounds retain the biological relevance of NPs but are not yet linked to bioactivities and may therefore be best evaluated by unbiased screening methods resulting in the identification of unexpected or unprecedented bioactivities. Herein, various NP fragments are combined with a tricyclic core connectivity via interrupted Fischer indole and indole dearomatization reactions to provide a collection of highly three-dimensional pseudo-NPs. Target hypothesis generation by morphological profiling via the cell painting assay guides the identification of an unprecedented chemotype for Aurora kinase inhibition with both its relatively highly 3D structure and its physicochemical properties being very different from known inhibitors. Biochemical and cell biological characterization indicate that the phenotype identified by the cell painting assay corresponds to the inhibition of Aurora kinase B. Various NP fragments are synthetically combined with a tricyclic core connectivity via interrupted Fischer indole and indole dearomatization reactions to provide a collection of highly three-dimensional pseudo-natural products. Target hypothesis generation by morphological profiling guides the identification of a truly unprecedented chemotype for Aurora kinase inhibition with both its relatively highly three-dimentional structure and its physicochemical properties being very different from known inhibitors. image