Small-molecule inhibitors of IL-2/IL-2R: lessons learned and applied.
The IL-2:IL-2R protein-protein interaction is of central importance to both healthy and diseased immune responses, and is one of the earliest examples of successful small-molecule inhibitor discovery against this target class. Drug-like inhibitors of IL-2 have been identified through a combination of fragment discovery, structure-based design, and medicinal chemistry; this discovery approach illustrates the importance of using a diverse range of complementary screening methods and analytical tools to achieve a comprehensive understanding of molecular recognition. The IL-2 story also provides insight into the dynamic nature of protein-protein interaction surfaces, their potential druggability, and the physical and chemical properties of effective small-molecule ligands. These lessons, from IL-2 and similar discovery programs, underscore an increasing awareness of the principles governing the development of drugs for protein-protein interactions.
Wilson
C G M
CG
Small Molecule Discovery Center, University of California, San Francisco, CA 94158, USA.
Arkin
M R
MR
D015195:Drug Design; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008222:Lymphokines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D013329:Structure-Activity Relationship
D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D008024:Ligands; D008222:Lymphokines; C046147:interleukin 2 inhibitor