title: Discovery of a potent small molecule IL-2 inhibitor through fragment assembly.
abstract: 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.
authors.affiliation: Sunesis Pharmaceuticals, 341 Oyster Point Boulevard, South San Francisco, California 94080, USA. braisted@sunesis.com
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Braisted
authors.forename: Johan D
authors.initials: JD
authors.lastname: Oslob
authors.forename: Warren L
authors.initials: WL
authors.lastname: Delano
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hyde
authors.forename: Robert S
authors.initials: RS
authors.lastname: McDowell
authors.forename: Nathan
authors.initials: N
authors.lastname: Waal
authors.forename: Chul
authors.initials: C
authors.lastname: Yu
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.forename: Brian C
authors.initials: BC
authors.lastname: Raimundo
mesh_terms: 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
chemical_list: D000480:Alkynes; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D010446:Peptide Fragments; D010880:Piperidines; D018123:Receptors, Interleukin; C474100:Ro26-4550