Discovery of a potent small molecule IL-2 inhibitor through fragment assembly.
Using a site-directed fragment discovery method called tethering, we have identified a 60 nM small molecule antagonist of a cytokine/receptor interaction (IL-2/IL2Ralpha) with cell-based activity. Starting with a low micromolar hit, we employed a combination of tethering, structural biology, and computational analysis to design a focused set of 20 compounds. Eight of these compounds were at least 5-fold more active than the original hit. One of these compounds showed a 50-fold enhancement and represents the highest affinity inhibitor reported against this protein-protein target class. This method of coupling selected fragments with a low micromolar hit shows great potential for generating high-affinity lead compounds.
Braisted
Andrew C
AC
Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, California 94080, USA. braisted@sunesis.com
Oslob
Johan D
JD
Delano
Warren L
WL
Hyde
Jennifer
J
McDowell
Robert S
RS
Waal
Nathan
N
Yu
Chul
C
Arkin
Michelle R
MR
Raimundo
Brian C
BC
D000480:Alkynes / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit; D007700:Kinetics; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D018123:Receptors, Interleukin / Q000819:agonists; D013329:Structure-Activity Relationship
D000480:Alkynes; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D010446:Peptide Fragments; D010880:Piperidines; D018123:Receptors, Interleukin; C474100:Ro26-4550