title: Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of IL-2: an approach for inhibiting protein-protein interactions.
abstract: Fragment assembly has shown promise for discovering small-molecule antagonists for difficult targets, including protein-protein interactions. Here, we describe a process for identifying a 60 nM inhibitor of the interleukin-2 (IL-2)/IL-2 receptor (IL-2Ralpha) interaction. By use of fragment-based approaches, a compound with millimolar affinity was evolved to a hit series with low micromolar activity, and these compounds were optimized into a lead series with nanomolar affinity. Fragment assembly was useful not only for hit identification, but also for lead optimization. Throughout the discovery process, biophysical methods and structural biology demonstrated that compounds bound reversibly to IL-2 at the IL-2 receptor binding site.
authors.affiliation: Sunesis Pharmaceuticals Inc., 341 Oyster Point Boulevard, South San Francisco, CA 94080, USA. raimondo@sunesis.com
authors.forename: Brian C
authors.initials: BC
authors.lastname: Raimundo
authors.forename: Johan D
authors.initials: JD
authors.lastname: Oslob
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Braisted
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hyde
authors.forename: Robert S
authors.initials: RS
authors.lastname: McDowell
authors.forename: Mike
authors.initials: M
authors.lastname: Randal
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Waal
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wilkinson
authors.forename: Chul H
authors.initials: CH
authors.lastname: Yu
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
mesh_terms: D000114:Acetylene / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D053645:Interleukin-2 Receptor alpha Subunit; D051379:Mice; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D001555:Benzene Derivatives; D004151:Dipeptides; C508017:IL2RA protein, human; C508018:Il2ra protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D010880:Piperidines; D011720:Pyrazoles; D018123:Receptors, Interleukin; D000114:Acetylene