High-affinity small molecule inhibitors of T cell costimulation: compounds for immunotherapy.
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.
Huxley
Philip
P
Avidex Limited, Abingdon, United Kingdom.
Sutton
Deborah H
DH
Debnam
Phillip
P
Matthews
Ian R
IR
Brewer
Joanna E
JE
Rose
Jennifer
J
Trickett
Matthew
M
Williams
Daniel D
DD
Andersen
Torben B
TB
Classon
Brendan J
BJ
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
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