Researchers at Progenra, Inc. has published the advanced online publication of the article “Selective Dual Inhibitors of the Cancer-related Deubiquitylating Proteases USP7 and USP47” (Weinstock, J. et al, ACS Medicinal Chemistry Letters). The new article presents evidence of a therapeutic benefit resulting from dual inhibition of USP7 and a related enzyme, USP47.

Additionally, data presented in this publication amplify the recent work published by Progenra and the Dana Farber Cancer Institute, showing that the parent compound of this series blocks USP7 activity in cells and exhibits antitumor activity in bortezomib-resistant myeloma models (Chauhan et al., Cancer Cell 22 (2012), 345-358).

Lead author Dr Joseph Weinstock directed medicinal chemistry as part of Progenra’s USP7 inhibitor preclinical development program. Structure-activity relationship data from the studies demonstrate that inhibition of USP7 correlates with that of USP47, and that these two deubiquitylases are uniquely sensitive to this chemical series. This result is significant because among the ~80 known deubiquitylases, USP7 and USP47 are very closely related and USP7 and USP47 exert non-overlapping anticancer cell effects. The latter, according to Dr Weinstock, may explain why a dual inhibitor of modest potency has antitumor efficacy in multiple animal models.

Progenra’s president & CEO, Dr Tauseef Butt commented, “We are excited by the data that Joe and the team have generated. Besides exhibiting therapeutic synergy, dual inhibitors whose targets have independent cellular mechanisms should be less susceptible than single target agents to resistance, a major impediment to a successful therapeutic outcome.”

Progenra is actively pursuing small molecule inhibition of USP7, a validated anticancer target that has been shown to stabilize oncogenic proteins and promote degradation of tumor suppressors (p53). USP7 inhibition should be efficacious against p53 wild type and mutant tumors owing to the enzyme’s range of cancer-promoting targets. The related DUB USP47 is also an anticancer target, affecting activity of DNA polymerase ß, which is involved in DNA repair. Early scaffolds in Progenra’s USP7 programme have demonstrated proof of concept in tumor models.

Progenra aims to discover and develop novel medicines exploiting ubiquitin pathways. Utilizing the company’s UbiPro Drug Discovery Platform, Progenra and its partners have identified novel modulators of therapeutically relevant ubiquitin targets.