Ubiquigent collaborates with University of Glasgow on structural basis for the mechanism of action of clinical USP1 inhibitor

Dundee, UK, 28 May 2024: Ubiquigent Limited (Ubiquigent), a drug discovery and development company harnessing novel deubiquitinase (DUB) modulators as new therapeutics for areas of high unmet medical need, today announced the release of a joint publication in bioRxiv, “Structural and biochemical insights on the mechanism of action of the clinical USP1 inhibitor, KSQ-4279”¹.

In the study, Ubiquigent, in collaboration with Professor Helen Walden’s group at the University of Glasgow, solved the structure of KSQ-4279 within the USP1/UAF1-substrate complex using cryo-EM. The study revealed that both KSQ-4279 and ML323 (an early USP1 inhibitor tool compound) bind to the same cryptic site of USP1, but disrupt the protein structure in subtly different ways. Inhibitor binding drives a substantial increase in thermal stability of USP1, which may be mediated through the inhibitors filling a hydrophobic tunnel in USP1.

Dr Sheelagh Frame, Chief Scientific Officer at Ubiquigent, said: “We are delighted to have collaborated with colleagues at the University of Glasgow to contribute to this study and understand the mode of binding of the clinical USP1 inhibitor. There are currently 5 USP1 inhibitors in clinical development and a large number in preclinical development. It is our hope that these insights will assist in informing the design of the next generation of USP1 inhibitors which may overcome the resistance to PARP inhibitors in patients with BRCA1/2 mutations.”

Prof Helen Walden, Professor of Structural Biology at the University of Glasgow and SAB member at Ubiquigent and, commented: “DUBs have emerged as an exciting new drug target, particularly in oncology, given their involvement in the ubiquitin-proteasome system. Through our collaboration with Ubiquigent, we have successfully identified the structure of a clinical USP1 inhibitor with its target at a molecular level, offering novel insights into its mechanism of action. We look forward to additional opportunities to explore the structural basis of DUB inhibition together with Ubiquigent.”

1. https://www.biorxiv.org/content/10.1101/2024.05.16.594330v1