Identification of nonpeptidic small-molecule inhibitors of interleukin-2.
The identification, design, and synthesis of a series of novel sulfamide- and urea-based small-molecule antagonists of the protein-protein interaction IL-2/IL-2Ralpha are described. Installation of a furan carboxylic acid fragment onto a low-micromolar sulfamide resulted in a 23-fold improvement in activity, providing a sub-micromolar, nonpeptidic IL-2 inhibitor (IC(50)=0.60 microM).
Waal
Nathan D
ND
Sunesis Pharmaceuticals, Inc., 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA. nwaal@sunesis.com
Yang
Wenjin
W
Oslob
Johan D
JD
Arkin
Michelle R
MR
Hyde
Jennifer
J
Lu
Wanli
W
McDowell
Robert S
RS
Yu
Chul H
CH
Raimundo
Brian C
BC
D006801:Humans; D020128:Inhibitory Concentration 50; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000737:chemistry / Q000494:pharmacology
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D013451:Sulfonic Acids; D014508:Urea; C005741:sulfamic acid