TY  - JOUR
AB  - Type 2 diabetes mellitus (T2DM) is a serious public health problem. In this review, we discuss current and promising future drugs, targets, in vitro assays and emerging omics technologies in T2DM. Importantly, we open the perspective to image-based high-content screening (HCS), with the focus of combining it with metabolomics or lipidomics. HCS has become a strong technology in phenotypic screens because it allows comprehensive screening for the cell-modulatory activity of small molecules. Metabolomics and lipidomics screen for perturbations at the molecular level. The combination of these data-intensive comprehensive technologies is enabled by the rapid development of artificial intelligence. It promises a deep cellular and molecular phenotyping directly linked to chemical information about the applied drug candidates or complex mixtures.
AU  - Zhang, X.
AU  - Kupczyk, E.
AU  - Schmitt-Kopplin, P.
AU  - Müller, C.
C1  - 66026
C2  - 52551
TI  - Current and future approaches for in vitro hit discovery in diabetes mellitus.
JO  - Drug Discov. Today
VL  - 27
IS  - 10
PY  - 2022
SN  - 1359-6446
ER  - 

TY  - JOUR
AB  - While target-based drug discovery strategies rely on the precise knowledge of the identity and function of the drug targets, phenotypic drug discovery (PDD) approaches allow the identification of novel drugs based on knowledge of a distinct phenotype. Image-based high-content screening (HCS) is a potent PDD strategy that characterizes small-molecule effects through the quantification of features that depict cellular changes among or within cell populations, thereby generating valuable data sets for subsequent data analysis. However, these data can be complex, making image analysis from large HCS campaigns challenging. Technological advances in image acquisition, processing, and analysis as well as machine-learning (ML) approaches for the analysis of multidimensional data sets have rendered HCS as a viable technology for small-molecule drug discovery. Here, we discuss HCS concepts, current workflows as well as opportunities and challenges of image-based phenotypic screening and data analysis.
AU  - Lin, S.
AU  - Schorpp, K.K.
AU  - Rothenaigner, I.
AU  - Hadian, K.
C1  - 59512
C2  - 48874
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 1348-1361
TI  - Image-based high-content screening in drug discovery.
JO  - Drug Discov. Today
VL  - 25
IS  - 8
PB  - Elsevier Sci Ltd
PY  - 2020
SN  - 1359-6446
ER  - 

TY  - JOUR
AB  - Synergistic drug combinations are commonly sought to overcome monotherapy resistance in cancer treatment. To identify such combinations, high-throughput cancer cell line combination screens are performed; and synergy is quantified using competing models based on fundamentally different assumptions. Here, we compare the behaviour of four synergy models, namely Loewe additivity, Bliss independence, highest single agent and zero interaction potency, using the Merck oncology combination screen. We evaluate agreements and disagreements between the models and investigate putative artefacts of each model's assumptions. Despite at least moderate concordance between scores (Pearson's r >0.32, Spearman's rho > 0.34), multiple instances of strong disagreement were observed. Those disagreements are driven by, among others, large differences in tested concentrations, maximum response values and median effective concentrations.
AU  - Vlot, A.H.C.*
AU  - Aniceto, N.*
AU  - Menden, M.P.
AU  - Ulrich-Merzenich, G.*
AU  - Bender, A.*
C1  - 56981
C2  - 47447
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 2286-2298
TI  - Applying synergy metrics to combination screening data: Agreements, disagreements and pitfalls.
JO  - Drug Discov. Today
VL  - 24
IS  - 12
PB  - Elsevier Sci Ltd
PY  - 2019
SN  - 1359-6446
ER  - 

TY  - JOUR
AB  - © 2017 Elsevier Ltd. The International Knockout Mouse Consortium (IKMC) developed high throughput gene trapping and gene targeting pipelines that produced mostly conditional mutations of more than 18,500 genes in C57BL/6N mouse embryonic stem (ES) cells which have been archived and are freely available to the research community as a frozen resource. From this unprecedented resource more than 6000 mutant mouse strains have been generated by the IKMC in collaboration with the International Mouse Phenotyping Consortium (IMPC). In addition, a cre-driver resource was established including 250 C57BL/6 cre-inducible mouse strains. Complementing the cre-driver resource, a collection comprising 27 rAAVs expressing cre in a tissue-specific manner has also been produced. All resources are easily accessible from the IKMC/IMPC web portal (www.mousephenotype.org). The IKMC/IMPC resource is a standardized reference library of mouse models with defined genetic backgrounds enabling the analysis of gene-disease associations in mice of different genetic makeup and should therefore have a major impact on biomedical research.
AU  - Kaloff, C.
AU  - Anastassiadis, K.*
AU  - Ayadi, A.*
AU  - Baldock, R.*
AU  - Beig, J.
AU  - Birling, M.C.*
AU  - Bradley, A.*
AU  - Brown, S.D.M.*
AU  - Bürger, A.
AU  - Bushell, W.*
AU  - Chiani, F.*
AU  - Collins, F.S.*
AU  - Doe, B.*
AU  - Eppig, J.T.*
AU  - Finnell, R.H.*
AU  - Fletcher, C.*
AU  - Flicek, P.*
AU  - Fray, M.*
AU  - Friedel, R.H.*
AU  - Gambadoro, A.*
AU  - Gates, H.*
AU  - Hansen, J.
AU  - Herault, Y.*
AU  - Hicks, G.G.*
AU  - Hörlein, A.
AU  - Hrabě de Angelis, M.
AU  - Iyer, V.*
AU  - de Jong, P.J.*
AU  - Koscielny, G.*
AU  - Kühn, R.
AU  - Liu, P.*
AU  - Lloyd, K.C.K.*
AU  - Lopez, R.G.*
AU  - Marschall, S.
AU  - Martínez, S.*
AU  - McKerlie, C.*
AU  - Meehan, T.F.*
AU  - von Melchner, H.*
AU  - Moore, M.*
AU  - Murray, S.A.*
AU  - Nagy, A.*
AU  - Nutter, L.M.J.*
AU  - Pavlovic, G.*
AU  - Pombero, A.*
AU  - Prosser, H.*
AU  - Ramirez-Solis, R.*
AU  - Ringwald, M.*
AU  - Rosen, B.*
AU  - Rosenthal, N.*
AU  - Rossant, J.*
AU  - Ruiz Noppinger, P.*
AU  - Ryder, E.*
AU  - Skarnes, W.C.*
AU  - Schick, J.
AU  - Schnütgen, F.*
AU  - Schofield, P.*
AU  - Seisenberger, C.
AU  - Selloum, M.*
AU  - Smedley, D.*
AU  - Simpson, E.M.*
AU  - Stewart, A.F.*
AU  - Teboul, L.*
AU  - Tocchini Valentini, G.P.*
AU  - Valenzuela, D.*
AU  - West, A.P.*
AU  - Wurst, W.
C1  - 51973
C2  - 43611
TI  - Genome wide conditional mouse knockout resources.
JO  - Drug Discov. Today
PY  - 2017
SN  - 1359-6446
ER  - 

TY  - JOUR
AB  - Hypothalamic neural circuits are recognised as primary sites of the neuromodulator effect of homeostatic food intake, whereas changes in ventral tegmental area (VTA), hippocampus and amygdala have been implicated in the hedonic, cognitive and emotional aspects of eating. Here, we discuss synaptic transmission and plasticity within brain circuits governing appetite and food intake behaviour, focusing on the metabolic hormones ghrelin and leptin. We discuss functional changes within these circuitries and critically assess the applicability of electrophysiological measurements using in vitro multielectrode array (MEA) systems to identify novel appetite modulators. Stringent validation of functional assays to screen neuroactive substrates is of crucial importance for the discovery of novel food intake modulators, with major implications for the nutraceutical food industry and drug development.
AU  - Shaban, H.*
AU  - O'Connor, R.*
AU  - Ovsepian, S.V.
AU  - Dinan, T.G.*
AU  - Cryan, J.F.*
AU  - Schellekens, H.*
C1  - 49496
C2  - 40696
CY  - Oxford
SP  - 31-42
TI  - Electrophysiological approaches to unravel the neurobiological basis of appetite and satiety: Use of the multielectrode array as a screening strategy.
JO  - Drug Discov. Today
VL  - 22
IS  - 1
PB  - Elsevier Sci Ltd
PY  - 2017
SN  - 1359-6446
ER  -