Mission Therapeutics pipeline includes the following programmes:
USP30 is the only DUB that localises to the outer mitochondrial membrane. Consistent with this, it has been shown to have roles in both mitophagy and apoptosis in different contexts (Bingol et al., 2014 and Liang et al., 2015). As defective mitophagy has strong links with Parkinson’s disease, USP30 has been highlighted as a promising new target in the CNS arena. Similarly, USP30 is gaining attention as a target in the oncology setting as depletion of USP30 was shown to sensitise cancer cells to BCL2 inhibition. Thus, USP30 inhibitors have potential to synergise with BH3 mimetics or other agents that stimulate apoptotic pathways. Mission has developed potent, selective inhibitors of USP30 and is exploring their potential for treating Parkinson’s disease and cancer.
USP7 is a DUB with strong oncology links and is an established anti-cancer target. The rationale behind targetting USP7 is mainly due to its oncogenic activity as a regulator of the p53:HDM2 axis (Nicholson et al., 2011) although it has other oncogenic properties that make it an attractive target. For instance, USP7 has been shown to deubiquitylate the tumour suppressor PTEN resulting in nuclear exclusion and loss of function (Trotman et al., 2007, Song et al., 2008). It has also been implicated in controlling the suppressive capacity of regulatory T cells (Tregs) in vivo through regulating Foxp3 (van Loosdregt et al., 2013) and USP7 inhibition may induce immune-mediated killing of cancer cells. Given the recent success of immune-modulatory anti-cancer therapies in clinical trials, Mission will aim to validate this aspect of USP7 biology with its small molecule tools.
Additional DUB Programmes
In addition to the above programmes, Mission is pursuing a number of other DUB targets in oncology (including DNA Damage Response and Synthetic Lethal mechanisms), neurodegeneration and inflammation.