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https://www.readbyqxmd.com/read/29236775/active-site-targeted-covalent-irreversible-inhibitors-of-usp7-impair-the-functions-of-foxp3-t-regulatory-cells-by-promoting-ubiquitination-of-tip60
#1
Feng Wang, Liqing Wang, Jian Wu, Ivan Sokirniy, Phuong Nguyen, Thomas Bregnard, Joseph Weinstock, Michael Mattern, Irina Bezsonova, Wayne W Hancock, Suresh Kumar
Accumulation of Foxp3+ T-regulatory (Treg) cells in the tumor microenvironment is associated with tumor immune evasion and poor patient outcome in the case of many solid tumors. Current therapeutic strategies for blocking Treg functions are not Treg-specific, and display only modest and transient efficacy. Recent studies revealed that ubiquitin-specific protease 7 (USP7) is essential for Treg functions by stabilizing expression of Tip60 and Foxp3, which together are central to the development and maintenance of the Treg cell lineage...
2017: PloS One
https://www.readbyqxmd.com/read/29200206/discovery-and-characterization-of-highly-potent-and-selective-allosteric-usp7-inhibitors
#2
Gerald Gavory, Colin R O'Dowd, Matthew D Helm, Jakub Flasz, Elias Arkoudis, Anthony Dossang, Caroline Hughes, Eamon Cassidy, Keeva McClelland, Ewa Odrzywol, Natalie Page, Oliver Barker, Hugues Miel, Timothy Harrison
Given the importance of ubiquitin-specific protease 7 (USP7) in oncogenic pathways, identification of USP7 inhibitors has attracted considerable interest. Despite substantial efforts, however, the development of validated deubiquitinase (DUB) inhibitors that exhibit drug-like properties and a well-defined mechanism of action has proven particularly challenging. In this article, we describe the identification, optimization and detailed characterization of highly potent (IC50 < 10 nM), selective USP7 inhibitors together with their less active, enantiomeric counterparts...
December 4, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29168472/characterization-of-naturally-occurring-pentacyclic-triterpenes-as-novel-inhibitors-of-deubiquitinating-protease-usp7-with-anticancer-activity-in-vitro
#3
Bo Jing, Meng Liu, Li Yang, Hai-Yan Cai, Jie-Bo Chen, Ze-Xi Li, Xi Kou, Yun-Zhao Wu, Dong-Jun Qin, Li Zhou, Jin Jin, Hu Lei, Han-Zhang Xu, Wei-Wei Wang, Ying-Li Wu
Deubiquitinating protease USP7 is a promising therapeutic target for cancer treatment, and interest in developing USP7 inhibitors has greatly increased. In the present study, we reported a series of natural pentacyclic triterpenes with USP7 inhibitory activity in vitro. Among them, both the ursane triterpenes and oleanane triterpenes were more active than the lupine triterpenes, whereas ursolic acid was the most potent with IC50 of 7.0±1.5 μmol/L. Molecular docking studies showed that ursolic acid might occupy the ubiquitin binding pocket of USP7, with the 17-carboxyl group and 3-hydroxyl group playing a vital role in the USP7-ursolic acid interaction...
November 23, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29166018/discovery-of-small-molecule-inhibitors-of-ubiquitin-specific-protease-7-usp7-using-integrated-nmr-and-in-silico-techniques
#4
Paola Di Lello, Richard Pastor, Jeremy M Murray, Robert A Blake, Frederick Cohen, Terry D Crawford, Joy Drobnick, Jason Drummond, Lorna Kategaya, Tracy Kleinheinz, Till Maurer, Lionel Rouge, Xianrui Zhao, Ingrid Wertz, Chudi Ndubaku, Vickie Tsui
USP7 is a deubiquitinase implicated in destabilizing the tumor suppressor p53 and for this reason it has gained increasing attention as a potential oncology target for small molecule inhibitors. Herein we describe the biophysical, biochemical and computational approaches that led to the identification of 4-(2-aminopyridin-3-yl)-phenol compounds described by Kategaya et al.1 as specific inhibitors of USP7. Fragment based lead discovery (FBLD) by NMR combined with virtual screening and re-mining of biochemical high-throughput screening (HTS) hits led to the discovery of a series of ligands that bind in the "palm" region of the catalytic domain of USP7 and inhibit its catalytic activity...
November 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29079691/identified-selective-usp7-inhibitors-compete-with-ubiquitin-binding
#5
(no author information available yet)
Specific USP7 inhibitors stabilized p53 and exhibited toxicity in tumor cells in vitro and in vivo.
October 27, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29065837/usp7-target-validation-and-drug-discovery-for-cancer-therapy
#6
Jin Zhou, Jinzheng Wang, Chao Chen, Haoliang Yuan, Xiaoan Wen, Hongbin Sun
BACKGROUND: USP7 (ubiquitin specific protease 7, also known as HAUSP) is one of the deubiquitinating enzymes (DUB) that reverse ubiquitination and spare substrate proteins from degradation. METHODS: After a brief introduction of ubiquitin-proteasome system (UPS) and human DUB, this review focuses on the structural and functional complexity of USP7 in tumor development and progression. Afterwards, USP7's physiological regulatory mechanisms and manipulation strategies are elaborated...
October 20, 2017: Medicinal Chemistry
https://www.readbyqxmd.com/read/29056421/structure-guided-development-of-a-potent-and-selective-non-covalent-active-site-inhibitor-of-usp7
#7
Ilaria Lamberto, Xiaoxi Liu, Hyuk-Soo Seo, Nathan J Schauer, Roxana E Iacob, Wanyi Hu, Deepika Das, Tatiana Mikhailova, Ellen L Weisberg, John R Engen, Kenneth C Anderson, Dharminder Chauhan, Sirano Dhe-Paganon, Sara J Buhrlage
Deubiquitinating enzymes (DUBs) have garnered significant attention as drug targets in the last 5-10 years. The excitement stems in large part from the powerful ability of DUB inhibitors to promote degradation of oncogenic proteins, especially proteins that are challenging to directly target but which are stabilized by DUB family members. Highly optimized and well-characterized DUB inhibitors have thus become highly sought after tools. Most reported DUB inhibitors, however, are polypharmacological agents possessing weak (micromolar) potency toward their primary target, limiting their utility in target validation and mechanism studies...
September 28, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29056420/usp7-specific-inhibitors-target-and-modify-the-enzyme-s-active-site-via-distinct-chemical-mechanisms
#8
Alexandra Pozhidaeva, Gabrielle Valles, Feng Wang, Jian Wu, David E Sterner, Phuong Nguyen, Joseph Weinstock, K G Suresh Kumar, Jean Kanyo, Dennis Wright, Irina Bezsonova
USP7 is a deubiquitinating enzyme that plays a pivotal role in multiple oncogenic pathways and therefore is a desirable target for new anti-cancer therapies. However, the lack of structural information about the USP7-inhibitor interactions has been a critical gap in the development of potent inhibitors. USP7 is unique among USPs in that its active site is catalytically incompetent, and is postulated to rearrange into a productive conformation only upon binding to ubiquitin. Surprisingly, we found that ubiquitin alone does not induce an active conformation in solution...
October 4, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/29049989/the-usp7-inhibitor-p5091-induces-cell-death-in-ovarian-cancers-with-different-p53-status
#9
Mengying Wang, Yayun Zhang, Taishu Wang, Jinrui Zhang, Zhu Zhou, Yan Sun, Shanshan Wang, Yulin Shi, Xuelin Luan, Yingqiu Zhang, Yifei Wang, Yang Wang, Zhongwen Zou, Lan Kang, Han Liu
BACKGROUND/AIMS: Ovarian cancer is often diagnosed at later stages with poor prognosis. Recent studies have associated the expression of deubiquitylase USP7 with the survival of ovarian cancers. Being a cysteine protease, USP7 could become a target for pharmacological intervention. Therefore, in this study, we assessed the influence of its inhibitor P5091 on ovarian cancer cells. METHODS: Ovarian cancer cells were treated with P5091, and cell proliferation was measured with MTT assay; cell morphology was inspected under a phase-contrast microscope; cell cycle and cell death were examined by flow cytometry...
October 19, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29045831/usp7-is-a-tumor-specific-wnt-activator-for-apc-mutated-colorectal-cancer-by-mediating-%C3%AE-catenin-deubiquitination
#10
Laura Novellasdemunt, Valentina Foglizzo, Laura Cuadrado, Pedro Antas, Anna Kucharska, Vesela Encheva, Ambrosius P Snijders, Vivian S W Li
The tumor suppressor gene adenomatous polyposis coli (APC) is mutated in most colorectal cancers (CRCs), resulting in constitutive Wnt activation. To understand the Wnt-activating mechanism of the APC mutation, we applied CRISPR/Cas9 technology to engineer various APC-truncated isogenic lines. We find that the β-catenin inhibitory domain (CID) in APC represents the threshold for pathological levels of Wnt activation and tumor transformation. Mechanistically, CID-deleted APC truncation promotes β-catenin deubiquitination through reverse binding of β-TrCP and USP7 to the destruction complex...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045389/molecular-basis-of-usp7-inhibition-by-selective-small-molecule-inhibitors
#11
Andrew P Turnbull, Stephanos Ioannidis, Wojciech W Krajewski, Adan Pinto-Fernandez, Claire Heride, Agnes C L Martin, Louise M Tonkin, Elizabeth C Townsend, Shane M Buker, David R Lancia, Justin A Caravella, Angela V Toms, Thomas M Charlton, Johanna Lahdenranta, Erik Wilker, Bruce C Follows, Nicola J Evans, Lucy Stead, Cristina Alli, Vladislav V Zarayskiy, Adam C Talbot, Alexandre J Buckmelter, Minghua Wang, Crystal L McKinnon, Fabienne Saab, Joanna F McGouran, Hannah Century, Malte Gersch, Marc S Pittman, C Gary Marshall, Tony M Raynham, Mary Simcox, Lorna M D Stewart, Sheila B McLoughlin, Jaime A Escobedo, Kenneth W Bair, Christopher J Dinsmore, Tim R Hammonds, Sunkyu Kim, Sylvie Urbé, Michael J Clague, Benedikt M Kessler, David Komander
Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells...
October 26, 2017: Nature
https://www.readbyqxmd.com/read/29045385/usp7-small-molecule-inhibitors-interfere-with-ubiquitin-binding
#12
Lorna Kategaya, Paola Di Lello, Lionel Rougé, Richard Pastor, Kevin R Clark, Jason Drummond, Tracy Kleinheinz, Eva Lin, John-Paul Upton, Sumit Prakash, Johanna Heideker, Mark McCleland, Maria Stella Ritorto, Dario R Alessi, Matthias Trost, Travis W Bainbridge, Michael C M Kwok, Taylur P Ma, Zachary Stiffler, Bradley Brasher, Yinyan Tang, Priyadarshini Jaishankar, Brian R Hearn, Adam R Renslo, Michelle R Arkin, Frederick Cohen, Kebing Yu, Frank Peale, Florian Gnad, Matthew T Chang, Christiaan Klijn, Elizabeth Blackwood, Scott E Martin, William F Forrest, James A Ernst, Chudi Ndubaku, Xiaojing Wang, Maureen H Beresini, Vickie Tsui, Carsten Schwerdtfeger, Robert A Blake, Jeremy Murray, Till Maurer, Ingrid E Wertz
The ubiquitin system regulates essential cellular processes in eukaryotes. Ubiquitin is ligated to substrate proteins as monomers or chains and the topology of ubiquitin modifications regulates substrate interactions with specific proteins. Thus ubiquitination directs a variety of substrate fates including proteasomal degradation. Deubiquitinase enzymes cleave ubiquitin from substrates and are implicated in disease; for example, ubiquitin-specific protease-7 (USP7) regulates stability of the p53 tumour suppressor and other proteins critical for tumour cell survival...
October 26, 2017: Nature
https://www.readbyqxmd.com/read/28930533/53bp1-a-guardian-for-centrosomal-integrity
#13
Haeyoung Kim, Hyungshin Yim
53BP1 is known as a mediator in DNA damage response and a regulator of DNA double-stranded breaks (DSBs) repair. 53BP1 was recently reported to be a centrosomal protein and a binding partner of mitotic polo-like kinase 1 (Plk1). The stability of 53BP1, in response to DSBs, is regulated by its phosphorylation, deubiquitination, and ubiquitination. During mitosis, 53BP1 is stabilized by phosphorylation at S380, a putative binding region with polo-box domain of Plk1, and deubiquitination by ubiquitin-specific protease 7 (USP7)...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28900000/correction-for-lecona-et-al-usp7-cooperates-with-scml2-to-regulate-the-activity-of-prc1
#14
Emilio Lecona, Varun Narendra, Danny Reinberg
No abstract text is available yet for this article.
October 1, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28807012/protein-deubiquitinase-usp7-is-required-for-osteogenic-differentiation-of-human-adipose-derived-stem-cells
#15
Yiman Tang, Longwei Lv, Wenyue Li, Xiao Zhang, Yong Jiang, Wenshu Ge, Yongsheng Zhou
BACKGROUND: Human adipose-derived stem cells (hASCs) are multipotent progenitor cells with self-renewal capabilities and multilineage differentiation potential, including osteogenesis. Although protein deubiquitinases have been linked to stem cell fate determination, whether protein deubiquitination contributes to lineage commitment during osteogenic differentiation of hASCs remains to be investigated. The objective of this study was to evaluate the effects of the ubiquitin specific protease 7 (USP7) on osteogenic differentiation of hASCs...
August 14, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28805676/inhibitors-of-deubiquitinating-enzymes-block-hiv-1-replication-and-augment-the-presentation-of-gag-derived-mhc-i-epitopes
#16
Christian Setz, Melanie Friedrich, Pia Rauch, Kirsten Fraedrich, Alina Matthaei, Maximilian Traxdorf, Ulrich Schubert
In recent years it has been well established that two major constituent parts of the ubiquitin proteasome system (UPS)-the proteasome holoenzymes and a number of ubiquitin ligases-play a crucial role, not only in virus replication but also in the regulation of the immunogenicity of human immunodeficiency virus type 1 (HIV-1). However, the role in HIV-1 replication of the third major component, the deubiquitinating enzymes (DUBs), has remained largely unknown. In this study, we show that the DUB-inhibitors (DIs) P22077 and PR-619, specific for the DUBs USP7 and USP47, impair Gag processing and thereby reduce the infectivity of released virions without affecting viral protease activity...
August 12, 2017: Viruses
https://www.readbyqxmd.com/read/28768102/chemical-approaches-to-intervening-in-ubiquitin-specific-protease-7-usp7-function-for-oncology-and-immune-oncology-therapies
#17
Jian Wu, Suresh Kumar, Feng Wang, Hui Wang, Lijia Chen, Patrick Arsenault, Michael Mattern, Joseph Weinstock
USP7, the most widely studied among the nearly 100 deubiquitinating enzymes, supports cancer by positively affecting tumor growth and negatively affecting the patient's immune response to tumors. Great interest exists, therefore, in developing USP7 inhibitors for clinical evaluation. While the proteasome inhibitor field has enjoyed clinical success, very few clinically appropriate effectors of deubiquitinating (protease) or ubiquitinating (ligase) enzymes have appeared. The ubiquitin protease/ligase field is moving from the initial discovery of potent, selective modulators with cell proof of concept and/or in vivo activity to the optimization of these molecules to impart drug-like properties or the discovery of new inhibitor scaffolds by improved screening or rational design...
August 2, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28767131/a-prognostic-mutation-panel-for-predicting-cancer-recurrence-in-stages-ii-and-iii-colorectal-cancer
#18
Shonan Sho, Colin M Court, Paul Winograd, Marcia M Russell, James S Tomlinson
BACKGROUND AND OBJECTIVES: Approximately 20-40% of stage II/III colorectal cancer (CRC) patients develop relapse. Clinicopathological factors alone are limited in detecting these patients, resulting in potential under/over-treatment. We sought to identify a prognostic tumor mutational profile that could predict CRC recurrence. METHODS: Whole-exome sequencing data were obtained for 207 patients with stage II/III CRC from The Cancer Genome Atlas. Mutational landscape in relapse-free versus relapsed cohort was compared using Fisher's exact test, followed by multivariate Cox regression to identify genes associated with cancer recurrence...
August 2, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28756477/p53-signaling-pathway-polymorphisms-cancer-risk-and-tumor-phenotype-in-tp53-r337h-mutation-carriers
#19
Gabriel S Macedo, Igor Araujo Vieira, Fernanda Salles Luiz Vianna, Barbara Alemar, Juliana Giacomazzi, Ana Paula Carneiro Brandalize, Maira Caleffi, Sahlua Miguel Volc, Henrique de Campos Reis Galvão, Edenir Inez Palmero, Maria Isabel Achatz, Patricia Ashton-Prolla
Li-Fraumeni and Li-Fraumeni-like syndrome (LFS/LFL) are clinically heterogeneous cancer predisposition syndromes characterized by diagnosis of early-onset and often multiple cancers with variable tumor patterns and incomplete penetrance. To date, the genetic modifiers described in LFS/LFL have been shown to map to either TP53 or its main negative regulator, MDM2. Additionally, all studies were focused on families with different TP53 germline mutations. Hence, in this study we explored the effect of the most studied polymorphisms of p53 pathway genes on clinical manifestations of individuals carrying the founder TP53 mutation R337H (n = 136) and controls (n = 186)...
July 29, 2017: Familial Cancer
https://www.readbyqxmd.com/read/28656291/usp7-is-associated-with-greater-disease-activity-in-systemic-lupus-erythematosus-via-stabilization-of-the-ifn%C3%AE-receptor
#20
Ying Yu, Zhaoliang Su, Zhejiong Wang, Huaxi Xu
An improved understanding of the mechanism of interferon (IFN)α activation in systemic lupus erythematosus (SLE) is likely to aid the identification of effective therapeutic targets. Increasing evidence has indicated that the activity of IFNα is mediated by the interplay of ubiquitylation/deubiquitylation enzyme regulators. The present study identified the deubiquitylation enzyme ubiquitin‑specific‑processing protease 7 (USP7) as a critical regulator of the human IFNα‑2 receptor (IFNAR1) protein levels...
August 2017: Molecular Medicine Reports
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