A High-Throughput Screen Reveals New Small-Molecule Activators and Inhibitors of Pantothenate Kinases

作者：Sharma Lalit Kumar; Leonardi Roberta; Lin Wenwei; Boyd Vincent A; Goktug Ash; Shelat Anang A; Chen Taosheng; Jackowski Suzanne; Rock Charles O^*

来源：Journal of Medicinal Chemistry, 2015, 58(3): 1563-1568.

DOI：10.1021/jm501585q

Pantothenate kinase (PanK) is a regulatory enzyme that controls coenzyme A (CoA) biosynthesis. The association of PanK with neurodegeneration and diabetes suggests that chemical modifiers of PanK activity may be useful therapeutics. We performed a high throughput screen of >520000 compounds from the St. Jude compound library and identified new potent PanK inhibitors and activators with chemically tractable scaffolds. The HTS identified PanK inhibitors exemplified by the detailed characterization of a tricyclic compound (7) and a preliminary SAR. Biophysical studies reveal that the PanK inhibitor acts by binding to the ATP-enzyme complex.

• 出版日期2015-2-12