Small-Molecule Inhibition of TNF-α-Reference-Cited by-同舟云学术

Small-Molecule Inhibition of TNF-α

Published:2005-11-11 Issue:5750 Volume:310 Page:1022-1025
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

He Molly M.¹²³⁴⁵,Smith Annemarie Stroustrup¹²³⁴⁵,Oslob Johan D.¹²³⁴⁵,Flanagan William M.¹²³⁴⁵,Braisted Andrew C.¹²³⁴⁵,Whitty Adrian¹²³⁴⁵,Cancilla Mark T.¹²³⁴⁵,Wang Jun¹²³⁴⁵,Lugovskoy Alexey A.¹²³⁴⁵,Yoburn Josh C.¹²³⁴⁵,Fung Amy D.¹²³⁴⁵,Farrington Graham¹²³⁴⁵,Eldredge John K.¹²³⁴⁵,Day Eric S.¹²³⁴⁵,Cruz Leslie A.¹²³⁴⁵,Cachero Teresa G.¹²³⁴⁵,Miller Stephan K.¹²³⁴⁵,Friedman Jessica E.¹²³⁴⁵,Choong Ingrid C.¹²³⁴⁵,Cunningham Brian C.¹²³⁴⁵

Affiliation:

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.

Abstract

We have identified a small-molecule inhibitor of tumor necrosis factor α (TNF-α) that promotes subunit disassembly of this trimeric cytokine family member. The compound inhibits TNF-α 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-α subunits.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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