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61.
Nicholas G.M. Davies Helen Browne Ben Davis Martin J. Drysdale Nicolas Foloppe Stephanie Geoffrey Ben Gibbons Terance Hart Roderick Hubbard Michael Rugaard Jensen Howard Mansell Andrew Massey Natalia Matassova Jonathan D. Moore James Murray Robert Pratt Stuart Ray Alan Robertson Stephen D. Roughley Joseph Schoepfer Paul Brough 《Bioorganic & medicinal chemistry》2012,20(22):6770-6789
Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design. 相似文献
62.
63.
An endopeptidase associated with bovine neurohypophysis secretory granules cleaves pro-ocytocin/neurophysin peptide at paired basic residues 总被引:2,自引:0,他引:2
C Clamagirand M Camier H Boussetta C Fahy A Morel P Nicolas P Cohen 《Biochemical and biophysical research communications》1986,134(3):1190-1196
The octacosapeptide sequence [Tyr18] pro-ocytocin/neurophysin (1-18)NH2 [pro-OT/Np(1-18)NH2] was synthesized and used as substrate to detect endoprotease(s) possibly involved in the processing of this precursor in bovine hypothalamo-neurohypophyseal tract. An endopeptidase (58 Kda) was detected in Lysates made from highly purified neurosecretory granules. This protease which cleaves the peptide bond on the carboxyl side of the Lys-Arg doublet, and no single basic residue, generates both OT-Gly10-Lys11-Arg12+Ala13-Val-Leu-Asp-Leu-Tyr18 (NH2) from the octacosapeptide substrate. In addition, a carboxypeptidase B-like activity converting OT-Gly10-Lys11-Arg12 into OT-Gly10 was detected in the same granule Lysates. It is hypothesized that a combination of these endoprotease and carboxypeptidase B-like activities together with the amidating enzyme of secretory granules might participate in the cleavage and processing of pro-OT/Np in vivo. 相似文献
64.
Sébastien Besseau Franziska Kellner Arnaud Lanoue Antje M.K. Thamm Vonny Salim Bernd Schneider Fernando Geu-Flores René H?fer Grégory Guirimand Anthony Guihur Audrey Oudin Ga?lle Glevarec Emilien Foureau Nicolas Papon Marc Clastre Nathalie Giglioli-Guivarc’h Benoit St-Pierre Danièle Werck-Reichhart Vincent Burlat Vincenzo De Luca Sarah E. O’Connor Vincent Courdavault 《Plant physiology》2013,163(4):1792-1803
65.
Nicolas Loeuille 《Functional ecology》2010,24(1):18-27
1. Selective pressures acting on foraging activities constrain the strength of interaction, hence the stability and energetic availability in food webs.
2. Because such selective pressures are usually measured at the individual level and because most experimental and theoretical works focus on simple settings, linking adaptive foraging with community scale patterns is still a far stretch.
3. Some recent models incorporate foraging adaptation in diverse communities. The models vary in the way they incorporate adaptation, via evolutionary or behavioural changes, and define individual fitness in various ways.
4. In spite of these differences, some general results linking adaptation to community structure and functioning emerge. In the present article, I introduce these different models and highlight their common results.
5. Adaptive foraging provides stability to large food web models and predicts successfully interaction patterns within food webs as well as other topological features such as food chain length.
6. The relationships between adaptive foraging and other structuring factors particularly depend on how well connected the local community is with surrounding communities (metacommunity aspect). 相似文献
2. Because such selective pressures are usually measured at the individual level and because most experimental and theoretical works focus on simple settings, linking adaptive foraging with community scale patterns is still a far stretch.
3. Some recent models incorporate foraging adaptation in diverse communities. The models vary in the way they incorporate adaptation, via evolutionary or behavioural changes, and define individual fitness in various ways.
4. In spite of these differences, some general results linking adaptation to community structure and functioning emerge. In the present article, I introduce these different models and highlight their common results.
5. Adaptive foraging provides stability to large food web models and predicts successfully interaction patterns within food webs as well as other topological features such as food chain length.
6. The relationships between adaptive foraging and other structuring factors particularly depend on how well connected the local community is with surrounding communities (metacommunity aspect). 相似文献
66.
Sylvie Rodrigues-Ferreira Anne Di Tommaso Ariane Dimitrov Sylvie Cazaubon Nadège Gruel Hélène Colasson André Nicolas Nathalie Chaverot Vincent Molinié Fabien Reyal Brigitte Sigal-Zafrani Benoit Terris Olivier Delattre Fran?ois Radvanyi Franck Perez Anne Vincent-Salomon Clara Nahmias 《PloS one》2009,4(10)
Background
Breast cancer is a heterogeneous disease that is not totally eradicated by current therapies. The classification of breast tumors into distinct molecular subtypes by gene profiling and immunodetection of surrogate markers has proven useful for tumor prognosis and prediction of effective targeted treatments. The challenge now is to identify molecular biomarkers that may be of functional relevance for personalized therapy of breast tumors with poor outcome that do not respond to available treatments. The Mitochondrial Tumor Suppressor (MTUS1) gene is an interesting candidate whose expression is reduced in colon, pancreas, ovary and oral cancers. The present study investigates the expression and functional effects of MTUS1 gene products in breast cancer.Methods and Findings
By means of gene array analysis, real-time RT-PCR and immunohistochemistry, we show here that MTUS1/ATIP3 is significantly down-regulated in a series of 151 infiltrating breast cancer carcinomas as compared to normal breast tissue. Low levels of ATIP3 correlate with high grade of the tumor and the occurrence of distant metastasis. ATIP3 levels are also significantly reduced in triple negative (ER- PR- HER2-) breast carcinomas, a subgroup of highly proliferative tumors with poor outcome and no available targeted therapy. Functional studies indicate that silencing ATIP3 expression by siRNA increases breast cancer cell proliferation. Conversely, restoring endogenous levels of ATIP3 expression leads to reduced cancer cell proliferation, clonogenicity, anchorage-independent growth, and reduces the incidence and size of xenografts grown in vivo. We provide evidence that ATIP3 associates with the microtubule cytoskeleton and localizes at the centrosomes, mitotic spindle and intercellular bridge during cell division. Accordingly, live cell imaging indicates that ATIP3 expression alters the progression of cell division by promoting prolonged metaphase, thereby leading to a reduced number of cells ungergoing active mitosis.Conclusions
Our results identify for the first time ATIP3 as a novel microtubule-associated protein whose expression is significantly reduced in highly proliferative breast carcinomas of poor clinical outcome. ATIP3 re-expression limits tumor cell proliferation in vitro and in vivo, suggesting that this protein may represent a novel useful biomarker and an interesting candidate for future targeted therapies of aggressive breast cancer. 相似文献67.
68.
The calcium/calmodulin-dependent protein kinase II (CaMKII) plays a key role in the induction of long-term postsynaptic modifications following calcium entry. Experiments suggest that these long-term synaptic changes are all-or-none switch-like events between discrete states. The biochemical network involving CaMKII and its regulating protein signaling cascade has been hypothesized to durably maintain the evoked synaptic state in the form of a bistable switch. However, it is still unclear whether experimental LTP/LTD protocols lead to corresponding transitions between the two states in realistic models of such a network. We present a detailed biochemical model of the CaMKII autophosphorylation and the protein signaling cascade governing the CaMKII dephosphorylation. As previously shown, two stable states of the CaMKII phosphorylation level exist at resting intracellular calcium concentration, and high calcium transients can switch the system from the weakly phosphorylated (DOWN) to the highly phosphorylated (UP) state of the CaMKII (similar to a LTP event). We show here that increased CaMKII dephosphorylation activity at intermediate Ca2+ concentrations can lead to switching from the UP to the DOWN state (similar to a LTD event). This can be achieved if protein phosphatase activity promoting CaMKII dephosphorylation activates at lower Ca2+ levels than kinase activity. Finally, it is shown that the CaMKII system can qualitatively reproduce results of plasticity outcomes in response to spike-timing dependent plasticity (STDP) and presynaptic stimulation protocols. This shows that the CaMKII protein network can account for both induction, through LTP/LTD-like transitions, and storage, due to its bistability, of synaptic changes. 相似文献
69.
Pierce RJ Dubois-Abdesselem F Caby S Trolet J Lancelot J Oger F Bertheaume N Roger E 《Memórias do Instituto Oswaldo Cruz》2011,106(7):794-801
Only one drug is currently available for the treatment and control of schistosomiasis and the increasing risk of selecting strains of schistosome that are resistant to praziquantel means that the development of new drugs is urgent. With this objective we have chosen to target the enzymes modifying histones and in particular the histone acetyltransferases and histone deacetylases (HDAC). Inhibitors of HDACs (HDACi) are under intense study as potential anti-cancer drugs and act via the induction of cell cycle arrest and/or apoptosis. Schistosomes like other parasites can be considered as similar to tumours in that they maintain an intense metabolic activity and rate of cell division that is outside the control of the host. We have shown that HDACi can induce apoptosis and death of schistosomes maintained in culture and have set up a consortium (Schistosome Epigenetics: Targets, Regulation, New Drugs) funded by the European Commission with the aim of developing inhibitors specific for schistosome histone modifying enzymes as novel lead compounds for drug development. 相似文献
70.