Targets in the ubiquitin-proteasome system (UPS) have generated successful marketed drugs, such as Velcade®, Revlimid® and Kyprolis®, that have revolutionized the treatment of previously intractable conditions such as multiple myeloma. The emergence of novel classes of drugs such as Protacs and E3 modulators hi-jacking the UPS to selectively degrade critical targets is expanding the scope of agents available to manage debilitating conditions.
Deubiquitinases (DUBs) are key enzymes involved in modulating protein stability, they belong to a relatively large family of approximately 100 enzymes usually acting upstream of the proteasome degradation machinery. As yet they have proved difficult to drug by conventional means although they hold out the promise of lower toxicity and access to a wider range of indications. In particular, we believe there is a chance that greater efficacy and treatment of solid tumors can be realized as well as provide multiple targets in the UPS beyond oncology.
Recognizing the unique therapeutic potential of the ubiquitin-proteasome system, Almac Discovery has developed a purpose-built, fully comprehensive assay and hit finding platform (Ubi-Plex®) with the aim of identifying and developing novel inhibitors for therapeutically relevant DUBs.
The platform has now been exploited internally for ~10 DUBs including USP7 and USP19. Small molecule inhibitors and fragments have been identified for a number of DUB programs and subsequently validated. These provide new exciting opportunities for medicinal chemistry. De novo target identification and validation efforts are also an integral part of this discovery platform to ensure sustainability and the development of truly innovative therapeutics. A combination of proprietary biochemical, biophysical, structural biology, computational chemistry, pharmacology, ADME and bioinformatic cascades of assays routinely support all our DUB programs.
The power and utility of Ubi-Plex® has now been illustrated by DUB inhibitors showing efficacy, exposure and safety in disease-relevant pre-clinical models.
Ubi-Plex® offers a rare opportunity to create a whole new world of therapeutics covering a wide range of therapeutic opportunities including, but not limited to, oncology, neurodegenerative disease, inflammation and metabolism.
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