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Science 310 (5750): 1022-1025

Copyright © 2005 by the American Association for the Advancement of Science

Small-Molecule Inhibition of TNF-{alpha}

Molly M. He,1 Annemarie Stroustrup Smith,2 Johan D. Oslob,1 William M. Flanagan,1 Andrew C. Braisted,1 Adrian Whitty,3 Mark T. Cancilla,1 Jun Wang,4 Alexey A. Lugovskoy,3 Josh C. Yoburn,1 Amy D. Fung,1 Graham Farrington,3 John K. Eldredge,3 Eric S. Day,3 Leslie A. Cruz,5 Teresa G. Cachero,3 Stephan K. Miller,3 Jessica E. Friedman,3 Ingrid C. Choong,1 Brian C. Cunningham1*

Abstract: We have identified a small-molecule inhibitor of tumor necrosis factor {alpha} (TNF-{alpha}) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-{alpha} activity in biochemical and cell-based assays with median inhibitory concentrations of 22 and 4.6 micromolar, respectively. Formation of an intermediate complex between the compound and the intact trimer results in a 600-fold accelerated subunit dissociation rate that leads to trimer dissociation. A structure solved by x-ray crystallography reveals that a single compound molecule displaces a subunit of the trimer to form a complex with a dimer of TNF-{alpha} subunits.

1 Sunesis Pharmaceuticals, Incorporated, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
2 Kravis Children's Hospital, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1198, New York, NY 10029, USA.
3 Department of Drug Discovery, BiogenIdec, 14 Cambridge Center, Cambridge, MA 02142, USA.
4 Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139–4307, USA.
5 Chemistry and Chemical Biology Program, University of California, San Francisco, 600 16th Street, Box 2280, San Francisco, CA 94143, USA.

* To whom correspondence should be addressed. E-mail: bcc{at}sunesis.com


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