1,720,957 research outputs found
Studies on Proteolysis Targeting Chimeras: platform technology for targeted protein degradation in drug discovery
No full textProteolysis Targeting Chimeras (PROTACs) represent an innovative approach to chemical
intervention into biology, with attractive therapeutic potential. In contrast to protein inhibition,
PROTACs trigger targeted protein degradation inside cells via hijacking the ubiquitinproteasome
machinery. PROTACs are bifunctional compounds composed by two small
molecules connected by a linker; one molecule binds to a protein of interest and the other one
binds to an E3 ubiquitin ligase. The ligases most commonly recruited are the von Hippel-
Lindau (VHL) protein complex CRL2VHL and the cereblon (CRBN) complex CRL4CRBN. To date,
different classes of target proteins have been successfully degraded, including epigenetic
targets such as bromodomain-containing proteins BRD2, BRD3, and BRD4, BRD9, TRIM24,
SIRT2, PCAF/GNC5, protein kinases, nuclear receptors and E3 ubiquitin ligases to selfdegrade.
The work described in this thesis is divided into two parts: the first part is about the research
activity carried out at the University of Dundee, under the supervision of Professor Alessio
Ciulli, while a second part involves the work done at the Department of Chemical Core
Technologies, within Nerviano Medical Sciences (Milan), under the supervision of Doctor
Eduard Felder.
The aim of the project carried out in Ciulli Lab was to investigate PROTAC-mediated
degradation of BRD7 and BRD9 proteins, subunits of the human SWI/SNF chromatin
remodelling complexes. These subunits have gained interest as therapeutic target especially in
hematopoietic cancers, for example supporting growth of acute myeloid leukemia (AML) cells.
Despite inhibitors able to disrupt the interaction of the BRD7/9 bromodomains are known, their
cellular activity has remained limited as other non-bromodomain functions of the target remain unaffected. PROTAC molecules able to induce BRD9 degradation would more profoundly
impact on BRD7 and BRD9 function and therefore could be used as chemical tools to better
understand its role in BAF complex and in oncogenesis.
Following analysis of the available co-crystal structures of the individual target and ligase
proteins with their respective ligands, a library of degraders has been designed and synthesised,
involving convergent synthetic strategies to conjugate a diverse range of scaffolds and linkers.
All compounds were tested in vitro against different cancer cell lines and immunoblotting was
carried out to assess the target degradation profile. VZ185 was found as a highly selective,
potent and rapid dual BRD7/BRD9 degrader, with slight preference for BRD9 over BRD7.
Degradation was demonstrated to be dependent upon proteasomal activity, cullin neddylation
and VHL binding.
The second section of the thesis reports the design, synthesis and biological characterization of
PROTACs targeting protein kinases, carried out at NMS for one-year stage. With the future
prospect of extending the development of PROTAC to other targets, it was planned to study a
literature example, in order to confirm the proof of concept. Amongst those available, we chose
DAS-6-2-2-6-CRBN, based on a potent tyrosine kinase inhibitor and a CRBN ligand that
induce degradation of c-ABL and BCR-ABL. Furthermore, we decided to extend the
development of degraders focusing on how target ligand and linker composition affect efficacy
and selectivity. The biological evaluation of the synthetized compounds was performed by the
Department of Biology of NMS throughout in vitro treatments of cancer cell lines and
immunoblotting
Hydrophilic and amphiphilic water-soluble dendrimer prodrugs suitable for parenteral administration of a non-soluble non-nucleoside HIV-1 reverse transcriptase inhibitor thiocarbamate derivative
No full textDrugs delivered by proper carriers enter into the cells much more rapidly and carry out their action much more promptly than in the free forms. A high drug concentration can be sustained for longer periods of time at the target site in the cell. In in vivo conditions, this would translate into a reduction of systemic toxicity, dosage and frequency of dosing. Dendritic polymers significantly affect drug delivery in terms of reaching the target site, modifying the bio-distribution of the drug, and enhancing the efficacy of different drugs including anticancer compounds. 2-([2-([(2-tolyl)amino]carbonothioyloxy)ethyl]aminocarbo-nyl)benzoic acid 1 is a thiocarbamate derivative belonging to an already reported class of non-nucleoside HIV-1 reverse transcriptase inhibitors. In in vitro assay it showed no cytotoxic effects but was endowed with very low solubility and poor activity against wild-type HIV-1 (EC50 = 27 μM). With the aim at improving its water solubility, 1 has been successfully incorporated inside non-toxic amino acids-modified core-shell hetero dendrimers. IR, NMR, zeta potential, mean size of particles, buffer capacity and in vitro release profile of prepared materials were reported. All dendriplexes were evaluated in cell-based assays to assess their cytotoxic profile. The obtained complexes, which harmonize a peripheral polycationic character and a buffer capacity which presuppose efficient cells penetration and increased residence time with a not PAMAM structured biodegradable scaffold, were well water-soluble and could rationally appear as a promising set of prodrugs for safe in vivo administrations
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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