Small molecule 4-1BB agonist for antitumor immunity

A small molecule that directly binds to the extracellular domain of the T cell costimulatory receptor 4-1BB and induces its oligomerization and signaling could help treat cancer by increasing the proliferation and effector and memory functions of antitumor T cells.

Screening of a chemical library in a human T cell line overexpressing 4-1BB identified a small molecule with a 1, 2, 4-oxadiazole scaffold, a hydrophobic 2-fluro phenyl moiety, and a hydrophilic benzoic acid group that activated 4-1BB. Further optimization of the molecule by replacing the hydrophobic 2-floro phenyl moiety with a naphthalene ring yielded a compound that activated 4-1BB signaling with an EC₅₀ of 64 nM, and increased T cell proliferation in the human T cell line compared with vehicle in a 4-1BB-dependent manner. ...