Ubiquitin Specific Proteases

Making drugs that Intervene in the complexity of protein degradation a reality.

Protein ubiquitination is an important post-translational modification with roles in a plethora of cellular processes including: proteolysis, gene expression, DNA repair, immune response, metabolism and cell-cycle regulation.  Dysregulation of the ubiquitin proteasome system (UPS) has also been implicated in the pathogenesis of multiple human diseases such as cancer, viral infection, metabolic or neurodegenerative disorders as well as immune and inflammatory-related medical conditions.

Almac Ubiquitin Specific Proteases

 

The approval and clinical success of the proteasome inhibitors Velcade® (bortezomib), Kyprolis® (carfilzomib), and Revlimid® (lenalidomide) for the treatment of mantle cell lymphoma and multiple myeloma has validated the ubiquitin proteasome system as a cancer target amenable for pharmacological intervention. Yet, however effective their clinical utility has been, it is severely limited due to poor selectivity and acute toxicity issues. By inhibiting the proteasome 26S subunit, the currently available proteasome inhibitors indiscriminately impair proteolysis in both cancer and normal cells and are therefore characterised by a low therapeutic index. To avoid this issue, a promising alternative approach involves targeting the ubiquitin-proteasome system upstream of the proteasome.  Interfering with the ubiquitin (Ub) conjugation/deconjugation machinery, for instance, at the level of the ubiquitin specific protease (USP), should allow for the development of improved therapeutics with enhanced specificity and reduced toxicity profiles. Furthermore, with over 60 USP family members Almac Discovery believe this is an emerging and attractive target class for pharmacological intervention.

Recognising the high therapeutic relevance and potential value of USP’s, Almac Discovery has developed and implemented a comprehensive, purpose-built and differentiated drug discovery platform against this target class.  This technology platform combines all elements and capabilities necessary to efficiently and rapidly create a stream of innovative products potentially addressing a broad range of high unmet medical needs.

Using the power of USP-ligand co-crystal structures we have developed multiple USP focussed screening libraries. These libraries are available for screening against internal and partner USP targets. In addition, comprehensive chemo- and bio-informatic analysis of the USP family coupled with siRNA screening has formed the basis of new target identification, and further guided library design.  We are now in a position to apply these approaches to identify USPs which control the stability of any therapeutically relevant targets of interest.

USP7

Almac Discovery first applied and validated its USP drug discovery platform on USP7 (also known as HAUSP).  These research activities lead to the rapid identification and optimisation of novel drug-like inhibitors of USP7.  These efforts demonstrated in turn, and for the first time, that genuine USP inhibitors with single digit nM potency and exquisite selectivity may indeed be achievable against this target class. Get in touch to request copies of our USP posters.

Partnering

Worldwide rights available please contact martin.wiles@almacgroup.com

Ubiquitin Specific Protease Resources

Hoeller D, Hecker C M, Dikic I, Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat. Rev. Cancer. 2006. 6, 776-788.

Gao G, Luo H, The ubiquitin-proteosome pathway in viral infections. J. Physiol.,Pharmacol. 2006. 84, 5-14

van Loosdregt J, Fleskens V, Fu J, Brenkman A B, Bekker C P J, Pals C E G M, Meerding J, Berkers C R, Barbi J, Gröne A, Sijts A j A M, Maurice M M, Kalkhoven E, Prakken B J, Ovaa H, Pan F, Zaiss D M W, Coffer P J, Stabilization of the Transcription Factor Foxp3 by the Deubiquitinase USP7 Increases Treg-Cell-Suppressive Capacity. Immunity.2013.39, 259-271

Rubinsztein, D C, The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443, 780-786

Corn J E, Vucic D, Ubiquitin in inflammation: the right linkage makes all the difference. Nat. Struct. & Mol. Biol. 2014. 21, 297-300

Nicholson B, Suresh Kumar KG. The multifaceted roles of USP7: new therapeutic opportunities. Cell Biochem. Biophys. 2011. 60, 61– 68

Kessler B M, Selective and reversible inhibitors of ubiquitin-specific protease 7: a patent evaluation (WO2013030218). Expert  Opin. Ther. Patents. 2014. 24, 1-6

Sheridan C, Drug makers target ubiquitin proteasome pathway anew. Nature Biotechnology. 2015. 33, 1115 – 1117

Ndubaku C, Tsui V, Inhibiting the Deubiquitinating Enzymes (DUBs). J. Med. Chem. 2014. 58, 1581 – 1595

Reyes Turcu F E, Ventii K H, Wilkinson K D, Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Ann. Rev. Biochem. 2009. 78, 363 -397