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J Med Chem. 2015 Feb 12;58(3):1563-8. doi: 10.1021/jm501585q. Epub 2015 Jan 21.

A high-throughput screen reveals new small-molecule activators and inhibitors of pantothenate kinases.

Author information

1
Department of Chemical Biology and Therapeutics, ‡Department of Infectious Diseases, St. Jude Children's Research Hospital , 262 Danny Thomas Place, Memphis, Tennessee 38105, United States.

Abstract

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.

PMID:
25569308
PMCID:
PMC4357395
DOI:
10.1021/jm501585q
[Indexed for MEDLINE]
Free PMC Article

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