Nature Structural & Molecular Biology
11, 67 - 72 (2004)
Published online: 29 December 2003; | doi:10.1038/nsmb711
Identification of small molecule inhibitors of anthrax lethal factorRekha G Panchal1, Ann R Hermone1, 5, Tam Luong Nguyen1, 5, Thiang Yian Wong2, Robert Schwarzenbacher2, James Schmidt3, Douglas Lane1, Connor McGrath1, Benjamin E Turk4, James Burnett1, M Javad Aman3, Stephen Little3, Edward A Sausville1, Daniel W Zaharevitz1, Lewis C Cantley4, Robert C Liddington2, Rick Gussio1
& Sina Bavari31
Developmental Therapeutics Program, NCI Frederick, Frederick, Maryland 21702-1201, USA. 2
The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA. 3
United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Frederick, Maryland 21702, USA. 4
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Room 1007, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. 5
These authors contributed equally to this work.
Correspondence should be addressed to Rekha G Panchal panchal@dtpax2.ncifcrf.gov or Sina Bavari bavaris@ncifcrf.govThe virulent spore-forming bacterium Bacillus anthracis secretes anthrax toxin composed of protective antigen (PA), lethal factor (LF) and edema factor (EF). LF is a Zn-dependent metalloprotease that inactivates key signaling molecules, such as mitogen-activated protein kinase kinases (MAPKK), to ultimately cause cell death. We report here the identification of small molecule (nonpeptidic) inhibitors of LF. Using a two-stage screening assay, we determined the LF inhibitory properties of 19 compounds. Here, we describe six inhibitors on the basis of a pharmacophoric relationship determined using X-ray crystallographic data, molecular docking studies and three-dimensional (3D) database mining from the US National Cancer Institute (NCI) chemical repository. Three of these compounds have K
i values in the 0.5−5  M range and show competitive inhibition. These molecular scaffolds may be used to develop therapeutically viable inhibitors of LF.
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