Science

Overview

Our team has the experience, expertise and determination to turn scientific advances in deubiquitylating enzymes (DUBs) into transformative therapies for serious illnesses including Parkinson’s Disease.

Mission Therapeutics has established a leadership position in deubiquitylating enzymes (‘DUBs’), which are attractive therapeutic targets as they are involved in many disease pathways and pathologies. Our principal target is a DUB called USP30, which can inhibit the normal process of mitophagy vital to maintaining healthy cells.

Mission is currently developing small molecule drugs which help restore normal mitophagy levels by retarding the action of USP30. As such, they ‘inhibit the inhibitor’ of mitophagy. USP30 is not Mission’s only DUB target: the company has built a world-leading proprietary multi-dimensional platform to generate first-in-class DUB inhibitors.

The basics

DUBs and the ubiquitin pathway

DUBs are key components of the ubiquitin pathway.

This pathway is present in all complex organisms and in virtually all cells in the human body, i.e. “ubiquitous”. It involves ubiquitylation, a major posttranslational modification process that selectively adds ubiquitin, a 76 amino acid regulatory polypeptide, onto target proteins. Ubiquitylation can influence a protein’s behaviour within cells in many different ways such as controlling protein homeostasis, protein activity, intracellular location, and sub-cellular turnover or degradation.

The addition of ubiquitin is carried out in three main steps – activation, conjugation and ligation – and involves a sequential cascade of the ubiquitin-activation enzyme (E1), ubiquitin conjugating enzymes (E2), and ubiquitin ligases (E3). This process can then be reversed through the activity of DUBs, a group of some 100 intracellular proteins that process, remove or recycle ubiquitin. The activities of DUBs thus regulate the functions of many proteins and their associated physiological pathways.

DUBs are attractive therapeutic targets

Through in-house research and extensive literature data searches, we are systematically exploring DUBs in areas with exceptional, novel biology and links to human pathology.

As outlined by our pipeline programs, we are currently focusing on developing DUB inhibitors for the treatment of several disease indications, including kidney disease, neurodegenerative disease, rare mitochondrial diseases and fibrosis. In November 2018, we also entered into a collaborative research and preclinical development program with AbbVie. This is focused on identifying specified DUB inhibitors, which are independent of our internal programs including USP30. Through our world-leading DUB drug discovery and development platform, we also have the potential to explore multiple additional DUB targets of relevance to other disease indications, both internally and through partnerships with biopharmaceutical companies. Mission and Pfizer entered into an evaluation and option agreement for DUB target validation in June 2020.

Role of the

ubiquitin pathway and inhibition of DUBs

As an integral part of the ubiquitin pathway, DUBs are involved in diverse cellular processes and in many disease pathologies. They play a central role in regulating protein homeostasis – that is, the cell’s balance between synthesizing proteins and recycling misfolded or dysfunctional proteins. As a result, modulation of ubiquitin-regulated pathways through DUB inhibition has significant relevance in many therapeutic areas (Harrigan J.A., Nat Rev Drug Discovery, 2017, Clague et al., 2013).

References:

By Mission scientists:

Harrigan J.A., Jacq, X., Martin, N. M., Jackson, S. (2017). Deubiquitylating enzymes (DUBs) and drug discovery: emerging opportunities. Nature Drug Discovery Reviews, 17, 57–78 (2018), doi:10.1038/nrd.2017.152

Zhang Fang, T., Sun, Y., Pearce, A. C., Eleuteri, S., Kemp, M., Luckhurst, C. A., Williams, R., Mills R., Almond, S., Burzynski, L., Márkus, N. M., Lelliott, C. J., Karp, N. A., Adams, D. J., Jackson, S. P., Zhao, J., Ganley, I. G., Thompson, P. W., Balmus, G., Simon, D. K. (2023) Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model. Nature Communications, 14, 7295

Others:

Hussain, S., Foreman, O., Perkins, S., Witzig, T., Miles, R., van Deursen, J. and Galardy, P. (2010). The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling. Leukemia, 24(9), pp.1641-1655.

Clague, M., Barsukov, I., Coulson, J., Liu, H., Rigden, D. and Urbe, S. (2013). Deubiquitylases From Genes to Organism. Physiological Reviews, 93(3), pp.1289-1315.

Pal , A.,. Young, M.A., and Donato, N.J. (2014). Emerging Potential of Therapeutic Targeting of UbiquitinSpecific Proteases in the Treatment of Cancer. Cancer Res 74:4955-4966.

Lopez-Castejon, G. and Edelmann, M.J (2016). Deubiquitinases: Novel Therapeutic Targets in Immune Surveillance? Mediators Inflammation 2016: 1-13.

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