Ubiquitin specific protease 7 (USP7) plays an important role in two important cancer pathways: it promotes the formation of regulatory T cells (Treg) that then block the immune response to the tumor; and it maintains low levels of p53, a prevalent tumor suppressor protein, thereby allowing the tumor to grow unchecked. USP7 is an enzyme that removes a tag (ubiquitin) from proteins. Ubiquitin marks proteins for destruction. By removing ubiquitin from a specialized regulatory protein called FOXP3 found within Treg, FOXP3 levels rise, increasing the number of Treg, suppressing the immune system. By removing ubiquitin from a protein called MDM2, p53 levels go down, thus allowing cancer cells to proliferate. By inhibiting USP7, two beneficial effects are elicited – increased immune system response to the tumor and tumor suppression by p53.

Potential for Best-in-Class Oral Small Molecule USP7 Inhibitors

We have developed a novel series of reversible, potent, highly-selective small molecule USP7 inhibitors that relieve Treg suppression both in vitro and in vivo. We have demonstrated that our USP7 inhibitors activate p53 in a cell-based assays and, importantly, block Treg-mediated suppression of CD8 T cells. In vivo proof of concept studies have demonstrated that our USP7 inhibitors increase inflammation and the tissue CD8/Treg ratio in a model of cell-mediated immunity. Furthermore, we observed a significant decrease in FOXP3 protein expression in tissue Treg isolated from treated animals. We believe our USP7 inhibitors are novel immunomodulators that destabilize FOXP3 in Treg to improve anti-tumor immunity in vivo.

We expect to select a clinical candidate in late 2018.