Small-molecule inhibition of TNF-alpha.
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.
He
Molly M
MM
Sunesis Pharmaceuticals, Incorporated, 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA.
Smith
Annemarie Stroustrup
AS
Oslob
Johan D
JD
Flanagan
William M
WM
Braisted
Andrew C
AC
Whitty
Adrian
A
Cancilla
Mark T
MT
Wang
Jun
J
Lugovskoy
Alexey A
AA
Yoburn
Josh C
JC
Fung
Amy D
AD
Farrington
Graham
G
Eldredge
John K
JK
Day
Eric S
ES
Cruz
Leslie A
LA
Cachero
Teresa G
TG
Miller
Stephan K
SK
Friedman
Jessica E
JE
Choong
Ingrid C
IC
Cunningham
Brian C
BC
D019921:Biotinylation; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D019281:Dimerization; D005453:Fluorescence; D006859:Hydrogen / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D013058:Mass Spectrometry; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
D007211:Indoles; D021122:Protein Subunits; D047888:Receptors, Tumor Necrosis Factor, Type I; C505854:SPD00000304; D014409:Tumor Necrosis Factor-alpha; D006859:Hydrogen