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Cambridge, United Kingdom

Itoh T.,University of Leicester | Itoh T.,Showa Pharmaceutical University | Fairall L.,University of Leicester | Muskett F.W.,University of Leicester | And 10 more authors.
Nucleic Acids Research | Year: 2015

Recent proteomic studies have identified a novel histone deacetylase complex that is upregulated during mitosis and is associated with cyclin A. This complex is conserved from nematodes to man and contains histone deacetylases 1 and 2, the MIDEAS corepressor protein and a protein called DNTTIP1 whose function was hitherto poorly understood. Here, we report the structures of two domains from DNTTIP1. The amino-terminal region forms a tight dimerization domain with a novel structural fold that interacts with and mediates assembly of the HDAC1:MIDEAS complex. The carboxy-terminal domain of DNTTIP1 has a structure related to the SKI/SNO/DAC domain, despite lacking obvious sequence homology. We show that this domain in DNTTIP1 mediates interaction with both DNA and nucleosomes. Thus, DNTTIP1 acts as a dimeric chromatin binding module in the HDAC1:MIDEAS corepressor complex. © 2015 The Author(s). Source

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. Source

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. Source

Jaspers J.E.,Netherlands Cancer Institute | Kersbergen A.,Netherlands Cancer Institute | Boon U.,Netherlands Cancer Institute | Sol W.,Netherlands Cancer Institute | And 17 more authors.
Cancer Discovery | Year: 2013

Inhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the P-glycoprotein drug efflux transporter. Here, we show that tumor-specific genetic inactivation of P-glycoprotein increases the long-term response of BRCA1-deficient mouse mammary tumors to olaparib, but these tumors eventually developed PARPi resistance. In a fraction of cases, this resistance is caused by partial restoration of homologous recombination due to somatic loss of 53BP1. Importantly, PARPi resistance was minimized by long-term treatment with the novel PARP inhibitor AZD2461, which is a poor P-glycoprotein substrate. Together, our data suggest that restoration of homologous recombination is an important mechanism for PARPi resistance in BRCA1-deficient mammary tumors and that the risk of relapse of BRCA1-deficient tumors can be effectively minimized by using optimized PARP inhibitors. © 2012 American Association for Cancer Research. Source

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.

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