Hottiger M.O.,University of Zürich |
Boothby M.,Vanderbilt University |
Koch-Nolte F.,University of Hamburg |
Luscher B.,RWTH Aachen |
And 5 more authors.
Science Signaling | Year: 2011
Adenosine 5′-diphosphate (ADP)-ribosylation is a protein posttranslational modification that is catalyzed by ADP-ribosyltransferases (ARTs), using nicotinamide adenine dinucleotide (NAD+) as a substrate. Mono-ribosylation can be extended into polymers of ADP-ribose (PAR). Poly(ADP-ribosyl)polymerase (PARP) 1, the best-characterized cellular enzyme catalyzing this process, is the prototypical member of a family of mono- and poly(ADP-ribosyl)transferases. The physiological consequences of ADP-ribosylation are inadequately understood. PARP2010, the 18th International Conference on ADP-Ribosylation, attracted scientists from all over the world to Zurich, Switzerland. Highlights from this meeting include promising clinical trials with PARP inhibitors and new insights into cell, structural, and developmental biology of ARTs and the (glyco)hydrolase proteins that catalyze de-ADP-ribosylation of mono- or poly-ADP-ribosylated proteins. Moreover, potential links to the NAD-dependent sirtuin family were explored on the basis of a shared dependence on cellular NAD+ concentrations and the relationship of ADP-ribosylation with intermediary metabolism and cellular energetics.
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.
Kemp M.,MISSION Therapeutics
Progress in Medicinal Chemistry | Year: 2015
This review examines the small molecules described over the past decade as inhibitors of any of the approximately 100 human deubiquitinating enzymes (DUBs). Structures from patent publications as well as from the primary literature are included. Inhibitors of two viral DUBs are also described since these proteases share structural similarity with one of the human DUB sub-families. The structure, function and disease associations of certain DUBs are presented. The evolution of the screening assays used to identify and characterise new inhibitors is discussed. Several emerging trends in the series are highlighted and the 'drug-likeness' of the various inhibitors is analysed. Large pharmaceutical company collaborations have drawn attention to this field, and these recent advances are discussed in the context of the wider range of therapeutically important DUB targets. © 2016 Elsevier B.V.
Jacq X.,MISSION Therapeutics |
Kemp M.,MISSION Therapeutics |
Martin N.M.B.,MISSION Therapeutics |
Jackson S.P.,MISSION Therapeutics |
Jackson S.P.,University of Cambridge
Cell Biochemistry and Biophysics | Year: 2013
Covalent post-translational modification of proteins by ubiquitin and ubiquitin-like factors has emerged as a general mechanism to regulate myriad intra-cellular processes. The addition and removal of ubiquitin or ubiquitin-like proteins from factors has recently been demonstrated as a key mechanism to modulate DNA damage response (DDR) pathways. It is thus, timely to evaluate the potential for ubiquitin pathway enzymes as DDR drug targets for therapeutic intervention. The synthetic lethal approach provides exciting opportunities for the development of targeted therapies to treat cancer: most tumours have lost critical DDR pathways, and thus rely more heavily on the remaining pathways, while normal tissues are still equipped with all DDR pathways. Here, we review key deubiquitylating enzymes (DUBs) involved in DDR pathways, and describe how targeting DUBs may lead to selective therapies to treat cancer patients. © 2013 The Author(s).
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.
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.
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.
MISSION Therapeutics | Date: 2012-02-14
Chemical and proteins for chemical and biological drug discovery, lead identification and diagnostics; chemical reagents; proteins, enzymes. Biological products for use in chemical and biological drug discovery, lead identification and diagnostics; biological products for therapeutic purposes; proteins for use in chemical and biological drug discovery, lead identification and diagnostics; therapeutic preparations; therapeutic preparations in the field of oncology and neurodegenerative diseases; anti-infectives; inhibitors; small molecule inhibitors. Software; databases; electronically stored data and media for storing such data. Bio-technology, pharmaceutical and scientific testing, research, development, advice, consultancy and information services; biological research; biology and chemistry services; pharmaceutical research services; drug discovery services; research and development services for lead identification; diagnostic services, namely analytical laboratory services; medicinal and synthetic chemistry services; research and development services in the creation of libraries or collections of biologicals, chemicals and compounds; research and development services relating to inhibiting enzymes and proteins; research and development services relating to targeting therapies to individuals; research and development services relating to combining therapies for individuals; research and development relating to enzymes and proteins; research and development relating to reagents.
News Article | December 5, 2016
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...