Find research datasets worth reusing
Search datasets from major research repositories and use ShareScore to quickly assess how well each record supports discovery, access, and reuse.
53
datasets available to search
ShareScore release 0.9.0
Dataset results
53 results for “Target Enabling Package”
Human DNA Cross-Link Repair 1A (DCLRE1A. SNM1A); A Target Enabling Package
<p>Cancer cells experience genomic instability, probably through a combination of excessive replicative activity and the loss of function of checkpoint and DNA repair pathways that may have contributed to the oncogenic transformation. Chemotherapy by DNA-damaging agents such as cisplatin and nitrogen mustards create DNA interstrand crosslinks (ICL), which can lead to double-strand breaks and cell death when the cells replicate their DNA. Genotoxic drugs are counteracted by the cell’s DNA damage response. Hence, it is expected that inhibiting DNA repair proteins would sensitise cells to chemotherapy.<br> Here we address an enzyme that participates in the repair of ICLs, DCLRE1A. The TEP includes expression clones and methods for producing the catalytic domain and high-throughput activity assays. Furthermore, we provide a crystallization system that generates thousands of reproducible crystals that allow soaking of small-molecule ligands. We provide crystal structures of several small molecule fragments and inhibitors, opening the way to development of more potent and selective inhibitors.</p>
Human Mixed- Lineage Leukemia, Translocated to 1 (MLLT1); A Target Enabling Package
<p>Overexpression of MLLT1 (also known as ENL, LTG19 and YEATS1) has recently been implicated as a driver of acute myeloid leukaemia (AML)(1, 2). Its epigenetic reader domain (dubbed YEATS domain) links histone acylation to gene expression via its role in the super elongation complex (SEC) (3) and its interaction with the histone methyl transferase DOT1L. Since epigenetic readers have been shown to be tractable targets for small molecule inhibitors, we have performed a library screen using a peptide displacement assay to identify inhibitors of MLLT1 interaction with acetylated histone tails. The screen yielded a potent hit and in further characterisation with biophysical methods it displayed a sub-micromolar KD for MLLT1 and its paralog MLLT3 (Also known as AF9) with no detectable binding to two other human YEATS proteins.</p>
Human Peroxisomal Coenzyme A Diphosphatase (NUDT7); A Target Enabling Package
<p>In an effort to characterise the human NUDIX family SGC Oxford has expressed recombinant human NUDT7 as part of the SGC chemical probe programme and solved the first crystal structure of this enzyme. This enabled a crystallographic fragment screen which in conjunction with a separate covalent fragment approach yielded a first-in-class small molecule inhibitor of NUDT7 with activity in the single-digit micromolar range in a catalytic assay. This compound paves the way for chemical probe development and further functional exploration of NUDT7 in physiological and disease contexts.</p>
Human Receptor-Interacting Serine/Threonine-Protein Kinase 2 (RIPK2); A Target Enabling Package
<p>RIPK2 inflammatory signalling downstream from the bacteria-sensing receptors NOD1 and NOD2 is associated with auto-immune and inflammatory conditions. RIPK2 inhibition has shown promise in disease models of inflammatory bowel disease and multiple sclerosis. In this TEP, we reveal a lack of correlation between inhibitor efficacy in cells and their potency using in vitro kinase assays. We show that RIPK2 kinase activity is in fact dispensable for NOD2 inflammatory signalling and that RIPK2 inhibitors function instead by antagonizing XIAP-binding and ubiquitination of RIPK2. We characterise the molecular basis for this effect. We also solved the first crystal structure of the RIPK2 kinase domain and applied a range of biochemical and cellular assays to profile type I and type II RIPK2 kinase inhibitors. Overall, our study illustrates how to target the ATP-binding pocket in RIPK2 to interfere with the RIPK2-XIAP interaction for modulation of NOD signalling.</p>
Human LIM domain kinase 1 (LIMK1), kinase domain; A Target Enabling Package
<p>Loss of the translational repressor FMRP in fragile X syndrome causes upregulation of the type II BMP receptor BMPR2 and its non-canonical signalling via the kinase LIMK1. LIMK1 performs inhibitory phosphorylation on cofilin proteins blocking their actin-severing activity. Excessive BMPR2-LIMK1 activation was associated with dendritic spine and behavioural defects in animal models that could be rescued by BMPR2 knockdown or LIMK1 inhibition. Here we present a target enabling package for the therapeutic target LIMK1. We include crystal structures of BMPR2, LIMK1, LIMK2 and the LIMK1-cofilin complex, as well as multiple assays for small molecule inhibitor screening. Finally, we identify a series of allosteric LIMK1 inhibitors with promising potency and selectivity that may potentially allow the development of a safe drug for this chronic indication.</p>
Human Kelch-like Protein 20 (KLHL20); A Target Enabling Package
<p>The BTB-Kelch protein KLHL20 is a hypoxia-induced CUL3-dependent E3 ligase linked to autophagy, Alzheimer’s disease and cancer. KLHL20 acts to terminate autophagy by promoting the ubiquitination and degradation of ULK1. KLHL20 is also reported as a top 20 biomarker for Alzheimer’s disease progression. Inhibition of KLHL20 may be neuroprotective by extending autophagy for the clearance of neurotoxic proteins aggregates. KLHL20 also promotes cancer through the ubiquitination and degradation of tumour suppressors including PML and DAPK1. We have solved the 1.1 Å structure of the Kelch domain of KLHL20 in complex with a DAPK1 peptide. We have used biophysical and cellular studies to validate this peptide site as a degron site for DAPK1 degradation. Using this peptide, we have also established alpha screen and HTRF assays to identify potent small molecule covalent inhibitors that compete with DAPK1 for binding to the Kelch domain of KLHL20.</p>
Human Galatose-1-phosphate Uridylyltransferase (GALT), Galactokinase 1 (GALK1); A Target Enabling Package
<p>This project describes a drug discovery plan for Classic Galactosemia, a rare disorder of galactose metabolism where there is currently no disease-transforming therapy. This TEP provides the protein reagents, biophysical assays, and structural information to facilitate two aspects of galactosemia research: (i) to understand the molecular basis of the disease due to defective GALT enzyme, and (ii) to provide chemical starting points to explore metabolic intervention of the upstream enzyme GALK1 aimed at mitigating the GALT defect (substrate reduction).</p>
Human 5'-Aminolevulinate Synthase, Erythroid-Specific (ALAS2); A Target Enabling Package
<p>Erythorid specific 5’-Aminolevulinate synthase (<a href="https://www.ncbi.nlm.nih.gov/gene/212">ALAS2</a>) catalyses the first and rate-determining step in haem biosynthesis during erythroid development. This TEP provides the structural biology tools to facilitate two aspects of ALAS2 research: (i) understanding how mutations in the ALAS2 C-terminus, a region unique to higher eukaryotes, lead to over-activity of the enzyme associated with a gain-of-function disorder; and (ii) providing chemical starting points to explore metabolic intervention of ALAS2, as substrate reduction therapy for the group of porphyria disorders that are associated with haem biosynthetic steps downstream of ALAS2.</p>
Human alpha-aminoadipic semialdehyde synthase (AASS); A Target Enabling Package
<p>This work provides the early tools to develop substrate reduction inhibitors for a genetic childhood seizure disorder, with the hypothesis to target the enzyme (AASS) upstream of the defective gene (ALDH7A1) in the human lysine metabolic pathway. This TEP package includes recombinant human AASS purification protocols, structures of the AASS second domain in different states, in vitro assays to detect ligand binding (differential scanning fluorimetry) and enzyme activity (NADH formation) of human AASS, as well as initial chemical matters.</p>
CAPN2: A Target Enabling Package
<p>CAPN2 mediates neurodegenerative effect through cleavage of a range of proteins linked to tau hyperphosphorylation (GSK-3β), higher levels of Aβ (NCX3), or poor memory (CPEB3). Inhibiting calpain-2 might reduce cleavage of these proteins and reverse its neurodegenerative effect. This aim of this TEP is to produce reagents to allow for further analysis of CAPN2 as a potential target for AD treatment.</p>
MDK: A Target Enabling Package
<p>Midkine (MDK) is a secreted heparan-sulfate binding cytokine and plays many roles in the development of disease pathology, particularly in neurodegeneration. It binds cell surface proteoglycans receptors via their chondroitin sulfate groups and its expression is regulated by retinoic acid. The roles of MDK are regulated by its interaction with heparan sulfate proteoglycans on the cell surface. From a pathological standpoint, proteomic analysis has shown it to be co-expressed with other amyloidogenic proteins, in addition to being highly colocalized in amyloid-beta plaques (2). <strong>The aim of this TEP is to generate reagents useful for investigating the role of MDK in Alzheimer’s disease, such as validation of available antibodies, generic knockout/knockdown cell lines and purified protein.</strong></p>
Nsp3 macrodomain of SARS-CoV-2 ; A Target Enabling Package
<p>The conserved macrodomain encoded as non-structural protein 3 (Nsp3 Mac1) is employed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to remove host-derived ribosylation, which is a post-translational modification involved in the production of antiviral cytokines. This TEP provides early tools to develop Nsp3 Mac1 inhibitors, including purification protocols of recombinant proteins, reproducible crystallisation condition suitable for X-ray crystallography fragment screening, biophysical (activity and binding) assays and over 200 fragment hits representing a wide range of chemotypes, that are a starting point for the development of more selective and potent compounds.</p>
PRDX1: A Target Enabling Package
<p>PRDXs are thiol-dependent peroxidases which catalyse the reduction of hydrogen peroxide, peroxynitrite and alkyl hydroperoxides. Peroxiredoxin-1 (PRDX1) is involved in modulating oxidative stress and exhibits cell specific expression in brain tissue. A pathological hallmark of neurodegenerative diseases includes progressive degenerative and neuronal death, which may be induced by an imbalance of reactive oxygen species. PRDX1 may therefore affect signalling pathways involved in neuroprotection and cell death by modulating oxidative stress. Several studies have shown a link between PRDX1 expression and Alzheimer’s disease. <strong>The aim of this project is to produce TEP reagents to help further understand the biology of PRDX1 in Alzheimer’s disease.</strong></p>
ScienceDex guides
Understand access before you commit
These curated guides explain access requirements, typical timelines, costs, and reuse considerations for widely used research datasets.
Allen Brain Atlas
Allen Brain Atlas is an Allen Institute collection of brain map atlases, datasets, APIs, and analysis tools covering mouse, human, and non-human primate brain resources.
Annotated Behaviour and Observability Dataset (ABODe)
ABODe is a University of Edinburgh DataShare dataset for behavior classification in group-housed mice using home-cage video, identities, bounding boxes, ground-plate positions, and annotator labels.
DANDI Archive for NWB datasets
DANDI is a BRAIN Initiative archive for publishing and sharing neurophysiology data, including electrophysiology, optophysiology, and behavioral data packaged as NWB and related standards.
International Brain Laboratory public data
The International Brain Laboratory public data releases expose standardized mouse decision-making experiments, including Neuropixels recordings, widefield calcium imaging, behavior, and session metadata accessed through the ONE API.
OpenNeuro
OpenNeuro is a free, open platform for sharing neuroimaging datasets, with public search, dataset pages, and download paths for web, S3, DataLad, and the OpenNeuro CLI.