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MISSION Therapeutics | Date: 2017-08-02

The present invention relates to novel compounds and methods for the manufacture of inhibitors of deubiquitylating enzymes (DUBs). In particular, the invention relates to the inhibition of ubiquitin C-terminal hydrolase L1 (UCHL1). The invention further relates to the use of DUB inhibitors in the treatment of cancer and other indications. Compounds of the invention include compounds having the formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 to R8 are as defined herein.


The present invention relates to materials and methods for high throughput monitoring of target engagement of isopeptidases, such as deubiquitylating enzymes by, inter alia, small molecule inhibitors. In particular the invention relates to development of high throughput assays to measure isopeptidase activity in biological samples, such as cells, animal tissues, animal tumours, human tissue or patient-derived biopsies.


News Article | June 27, 2017
Site: www.businesswire.com

CAMBRIDGE, England--(BUSINESS WIRE)--Mission Therapeutics, a drug discovery and development company focused on selectively targeting deubiquitylating enzymes (DUBs) to treat serious diseases including mitochondrial diseases, neurodegeneration, inflammation and cancer, today announced the formation of its inaugural Scientific Advisory Board (SAB). Mission’s co-founder and CSO, Professor Steve Jackson, FRS, FMedSci will chair the SAB, where he will be joined by four independent, internationally renowned scientists: Mission has built a leadership position and strength in the DUB field, and the SAB will provide strategic advice to the Company as it shapes and progresses its therapeutic programs and pipeline of first-in-class DUB inhibitors. On welcoming the members to the SAB, Dr. Anker Lundemose, Mission’s CEO, said: “We have attracted a prestigious group of experts to our Scientific Advisory Board, where they bring a wealth of experience across, cell signaling, posttranslational modifications, mitochondrial diseases, neurodegeneration and oncology. “The formation of this Board will help drive forward the clear clinical potential of our unique DUB platform for the production of first-in-class compounds targeting specific disease-associated DUBs for key indications where effective therapies are currently unavailable. The SAB members’ insights and guidance will prove invaluable as we prioritize and advance our programs.” For more information about the members of the SAB, see: http://missiontherapeutics.com/press-release/mission-therapeutics-appoints-scientific-advisory-board/ Mission Therapeutics is discovering and developing first-in-class therapeutics that inhibit disease-associated deubiquitylating enzymes (DUBs) involved in serious diseases including mitochondrial diseases, neurodegeneration, inflammation and cancer. Mission has built a proprietary world-leading DUB platform that is generating a rich pipeline of highly potent and specific small molecule drug candidates. These candidates have excellent clinical and commercial potential. Using patient selection strategies, the Company is now progressing several programs towards clinical development. The Company has strong collaborations with key academic and research centers including Cancer Research UK Laboratories & Gurdon Institute at University of Cambridge, Oxford Parkinson's Disease Centre at University of Oxford, and the Wellcome Trust Mitochondrial Research Centre at Newcastle University. In February 2016, Mission completed an $86m financing that was led by Touchstone Innovations and Woodford Patient Capital Trust, and included participation from existing investors Sofinnova Partners, Roche Venture Fund, Pfizer Venture Investments and SR One. Mission Therapeutics was founded in 2011 and its leadership team comprises international, commercial and scientific experience. The Company is based at the Babraham Research Campus, Cambridge, UK. Find out more about Mission Therapeutics at www.missiontherapeutics.com or follow @MISSIONTherapeu. DUBs comprise a group of around 100 proteins that play important roles in regulating ubiquitylation. This process is where ubiquitin – a small regulatory protein so called because it is present in all complex organisms and virtually every all cells in the body – controls protein homeostasis, protein activity, intracellular location, and sub-cellular turnover or degradation.


The present invention relates to materials and methods for high throughput monitoring of target engagement of isopeptidases, such as deubiquitylating enzymes by, inter alia, small molecule inhibitors. In particular the invention relates to development of high throughput assays to measure isopeptidase activity in biological samples, such as cells, animal tissues, animal tumours, human tissue or patient-derived biopsies.


CAMBRIDGE, England--(BUSINESS WIRE)--An article entitled “Deubiquitylating enzymes (DUBs) and drug discovery: emerging opportunities,” written by the drug discovery team at Mission Therapeutics was published online today in the scientific journal Nature Reviews Drug Discovery. The peer-reviewed article outlines how understanding the physiological and pathophysiological roles of human DUBs has accelerated over the past decade. It also highlights how elucidating the biological complexities of this enzyme family is providing opportunities for the development of potentially transformative therapies for a range of clinical indications. The article is authored by Company co-founders and scientists, including Dr Jeanine A. Harrigan and Professor Steve Jackson FRS. DUBs comprise a group of some 100 proteins that are known to play important roles in regulating ubiquitylation, the process whereby ubiquitin – a small protein so called because it is present in all complex organisms and virtually all cells in the body – controls protein homeostasis, protein activity, intracellular location, and sub-cellular turnover or degradation. The clinical development of DUB inhibitors initially proved challenging, in large part due to issues linked to specificity and selectivity. However, recent progress in DUB enzymology, biology and technological developments, described in the review, has confirmed that DUBs are druggable, novel therapeutic targets. As a result, first-generation inhibitors are now moving into, or are on the threshold of entering, patient trials in a number of clinical settings. Professor Steve Jackson, Co-Founder and CSO, Mission Therapeutics, and senior author on the paper, commented: “This article in Nature Reviews Drug Discovery covers seminal advances that have yielded critical insights into DUB target biology and chemistry over the past decade. A strong foundation in DUB research has been fundamental to Mission Therapeutics’ novel target validation and drug discovery platforms. To date, the platform has demonstrated the diverse clinical potential of novel chemistries selectively targeting different members of the DUB enzyme class.” Dr Anker Lundemose, Chief Executive Officer, Mission Therapeutics, added: “This review showcases Mission’s leadership position and strength in the DUB field. It also re-enforces the value of our proprietary DUB platform for the discovery and development of first-in-class drugs that selectively target specific disease-associated DUBs. We are now progressing several programmes through preclinical development exemplifying our platform’s translational potential.” Mission Therapeutics is an early-stage drug development company targeting the ubiquitin pathway for the treatment of neurodegenerative disease, fibrosis, inflammation, cancer and other diseases of unmet need. The Company has built a leading platform for the discovery and development of first-in-class, small-molecule drugs that selectively target deubiquitylating enzymes (DUBs) – an emerging drug class that is attracting significant commercial interest in the area of protein homeostasis. Mission has strong links with key academic and research centers, including Prof. Jackson’s Cancer Research UK Laboratories at the University of Cambridge Gurdon Institute, and leading UK centres in neurodegenerative diseases. The Company is managed by a team with broad international, commercial and clinical-science experience. In February 2016, the Company completed an $86m financing that was led by Imperial Innovations and Woodford Patient Capital Trust and included participation from existing investors Sofinnova Partners, Roche Venture Fund, Pfizer Venture Investments and SR One. Mission Therapeutics was founded in 2011 and is based at the Babraham Research Campus, Cambridge, UK.


Zhu Y.,Columbia University | Regunath K.,Columbia University | Jacq X.,MISSION Therapeutics | Prives C.,Columbia University
Genes and Development | Year: 2013

The interdependence of p53 and MDM2 is critical for proper cell survival and cell death and, when altered, can lead to tumorigenesis. Mitogen-activated protein kinase (MAPK) signaling pathways function in a wide variety of cellular processes, including cell growth, migration, differentiation, and death. Here we discovered that transforming growth factor β-activated kinase 1 (TAK1)-binding protein 1 (TAB1), an activator of TAK1 and of p38α, associates with and inhibits the E3 ligase activity of MDM2 toward p53 and its homolog, MDMX. Depletion of TAB1 inhibits MDM2 siRNA-mediated p53 accumulation and p21 induction, partially rescuing cell cycle arrest induced by MDM2 ablation. Interestingly, of several agents commonly used as DNA-damaging therapeutics, only cell death caused by cisplatin is mitigated by knockdown of TAB1. Two mechanisms are required for TAB1 to regulate apoptosis in cisplatin-treated cells. First, p38α is activated by TAB1 to phosphorylate p53 N-terminal sites, leading to selective induction of p53 targets such as NOXA. Second, MDMX is stabilized in a TAB1- dependent manner and is required for cell death after cisplatin treatment. Interestingly TAB1 levels are relatively low in cisplatin-resistant clones of ovarian cells and in ovarian patient's tumors compared with normal ovarian tissue. Together, our results indicate that TAB1 is a potential tumor suppressor that serves as a functional link between p53-MDM2 circuitry and a key MAPK signaling pathway. © 2013, Published by Cold Spring Harbor Laboratory Press.


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: Collaborative Research & Development | Award Amount: 1.89M | Year: 2015

MISSION Therapeutics, a UK-based SME is a world-leading expert in deubiquitylating enzyme (DUB) drug discovery, with a number of projects in lead optimisation. Through counter-screening our ongoing projects, we identified a small molecule inhibtiors of a DUB drug target with potential to be developed for treating soft tissue sarcomas and other cancers with clear unmet need and significant market potential. In this project we aim to pursue and develop these inhibitors with the overall objective of producing first-in-class DUB inhibitors as treatments for some of the most difficult to treat cancers.


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: Feasibility Study | Award Amount: 144.03K | Year: 2013

Novel therapies tailored for treatment of platinum-resistant ovarian cancer is an area of clear unmet need. Ovarian cancer is responsible for more deaths per year than any other cancer of the female reproductive system and developing drug resistance remains the main limitation of current chemotherapies. We propose an innovative approach to identifying novel drug targets for drug-resistant ovarian cancer that would exploit the very changes in the tumour that have led to the resistance. We propose to do this by screening all known human deubiquitylases (DUBs) – a novel, druggable class of enzymes – to identify innovative targets whose inhibition would selectively kill or re-sensitise drug-resistant ovarian tumours. The best validated targets will then enter the MISSION Therapeutics Ltd pipeline for further drug discovery efforts with a view to new, innovative and effective chemotherapies entering the clinic.


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: Feasibility Study | Award Amount: 149.62K | Year: 2014

Through work funded by the TSB, MISSION Therapeutics identified SENP enzymes as new therapeutic targets for treating drug-resistant ovarian cancer. For drug discovery, SENPs pose a distinct challenge as they require specific substrates and assays and they are not well studied in terms of their biological role(s). For these reasons, SENPS are currently considered higher risk targets. We propose to use our proven expertise targeting related enzymes to test the feasibility of developing SENP inhibitors by developing appropriate biochemical and cell-based activity assays then screening a bespoke compound library to assess druggability. In addition, we will carry out additional target validation to further assess the utility of inhibiting SENPs for treating drug-resistant cancers.


News Article | December 5, 2016
Site: www.prnewswire.com

CAMBRIDGE, England, December 5, 2016 /PRNewswire/ -- Michael Moore Transitions to Deputy Chairman Mission Therapeutics, a drug discovery and development company focused on selectively targeting deubiquitylating enzymes (DUBs) to treat cancer, neurodegenerative and other...

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