title: High-affinity small molecule inhibitors of T cell costimulation: compounds for immunotherapy.
abstract: Costimulatory molecules are important regulators of T cell activation and thus favored targets for therapeutic manipulation of immune responses. One of the key costimulatory receptors is CD80, which binds the T cell ligands, CD28, and CTLA-4. We describe a set of small compounds that bind with high specificity and low nanomolar affinity to CD80. The compounds have relatively slow off-rates and block both CD28 and CTLA-4 binding, implying that they occlude the shared ligand binding site. The compounds inhibit proinflammatory cytokine release in T cell assays with submicromolar potency, and as such, they represent promising leads for the development of novel therapeutics for immune-mediated inflammatory disease. Our results also suggest that other predominantly beta proteins, such as those that dominate the cell surface, may also be accessible as potentially therapeutic targets.
authors.affiliation: Avidex Limited, Abingdon, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Huxley
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Sutton
authors.forename: Phillip
authors.initials: P
authors.lastname: Debnam
authors.forename: Ian R
authors.initials: IR
authors.lastname: Matthews
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Brewer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rose
authors.forename: Matthew
authors.initials: M
authors.lastname: Trickett
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Williams
authors.forename: Torben B
authors.initials: TB
authors.lastname: Andersen
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Classon
mesh_terms: D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000187:drug effects / Q000276:immunology; D018122:B7-1 Antigen / Q000187:drug effects* / Q000276:immunology; D018106:CD28 Antigens / Q000187:drug effects / Q000276:immunology; D060908:CTLA-4 Antigen; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D007376:Interleukin-2 / Q000037:antagonists & inhibitors; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D015394:Molecular Structure; D008970:Molecular Weight; D011485:Protein Binding / Q000187:drug effects; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008024:Ligands; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma