Tumor necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins. This factor acts as a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease.
TNF is the target of several successful biologic drugs. Some TNF antagonists are efficacious in the clinic and have a well-documented mode of action. Additionally, most TNF antagonists belong to neutralizing antibodies, such as Infliximab, Etanercept, Adalimumab, Golimumab, and Certolizumab pegol.
Nonetheless, the use of biologics remains some restriction, as immunogenicity, supply chain complexity, and health economics. As a result, it is clear that more researches focus on molecule drugs of the anti-TNF biologics.
Here, we will introduce a potent small-molecule inhibitor of TNF, UCB-9260.
UCB-9260 binds to a pocket in the centre of the TNF trimer-formed by the movement of the TNF monomers. Besides, the compound stabilizes the distorted trimer and leads to reduced signaling through TNFR1.
In Hek-293 cells, UCB-9260 inhibits NF-κB with a geometric mean IC50 of 202 nM after TNF (10 pM) stimulation. In a cell cytotoxicity assay, UCB-9260 inhibits TNF-dependent cytotoxicity with a geometric mean IC50 of 116 nM using human TNF. Additionally, UCB-9260 inhibits TNF-dependent cytotoxicity with a geometric mean IC50 of 120 nM using mouse TNF.
In the aged 6-8 weeks adult male Balb/c CAIA model, UCB-9260 shows a significant reduction of the clinical score.
Besides, In order to test for TNF activity in vivo, using a TNF-dependent mouse model. The exogenous TNF-injection into the mouse peritoneal cavity can induce neutrophil recruitment. The result of flow cytometry shows that UCB-9260 significantly decreases CD45+GR1+ cells.
UCB-9260 inhibits TNF-induced neutrophil recruitment dose-dependently.
In conclusion, UCB-9260, an orally active compound, inhibits TNF signaling by stabilizing an asymmetric form of the trimer. Furthermore, UCB-9260 is selective for TNF over other superfamily members. And this has been tested in vitro and in vivo.
. O’Connell J, et al. Nat Commun. 2019 Dec 19;10(1):5795.