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# Marrying chemistry with biology by combining on-chip solution-based combinatorial synthesis and cellular screening

Nature Communications

Nature Publishing Group UK

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### Abstract

Drug development often relies on high-throughput cell-based screening of large compound libraries. However, the lack of miniaturized and parallelized methodologies in chemistry as well as strict separation and incompatibility of the synthesis of bioactive compounds from their biological screenings makes this process expensive and inefficient. Here, we demonstrate an on-chip platform that combines solution-based synthesis of compound libraries with high-throughput biological screenings (chemBIOS). The chemBIOS platform is compatible with both organic solvents required for the synthesis and aqueous solutions necessary for biological screenings. We use the chemBIOS platform to perform 75 parallel, three-component reactions to synthesize a library of lipidoids, followed by characterization via MALDI-MS, on-chip formation of lipoplexes, and on-chip cell screening. The entire process from the library synthesis to cell screening takes only 3 days and about 1 mL of total solutions, demonstrating the potential of the chemBIOS technology to increase efficiency and accelerate screenings and drug development.

### Abstract

High-throughput cell-based screening of compound libraries is utilised in drug development; however, a lack of compatible methods limits direct synthesis and testing. Here, the authors present a diverse chip based synthesis system which can be combined with cell screening and demonstrate the application.

### Most cited references24

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### The discovery of first-in-class drugs: origins and evolution.

(2014)
Analysis of the origins of new drugs approved by the US Food and Drug Administration (FDA) from 1999 to 2008 suggested that phenotypic screening strategies had been more productive than target-based approaches in the discovery of first-in-class small-molecule drugs. However, given the relatively recent introduction of target-based approaches in the context of the long time frames of drug development, their full impact might not yet have become apparent. Here, we present an analysis of the origins of all 113 first-in-class drugs approved by the FDA from 1999 to 2013, which shows that the majority (78) were discovered through target-based approaches (45 small-molecule drugs and 33 biologics). In addition, of 33 drugs identified in the absence of a target hypothesis, 25 were found through a chemocentric approach in which compounds with known pharmacology served as the starting point, with only eight coming from what we define here as phenotypic screening: testing a large number of compounds in a target-agnostic assay that monitors phenotypic changes. We also discuss the implications for drug discovery strategies, including viewing phenotypic screening as a novel discipline rather than as a neoclassical approach.
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### Author and article information

###### Contributors
levkin@kit.edu
###### Journal
Nat Commun
Nat Commun
Nature Communications
Nature Publishing Group UK (London )
2041-1723
28 June 2019
28 June 2019
2019
: 10
###### Affiliations
[1 ]ISNI 0000 0001 0075 5874, GRID grid.7892.4, Karlsruhe Institute of Technology (KIT), Institute of Toxicology and Genetics (ITG), ; Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
[2 ]ISNI 0000 0001 0664 9773, GRID grid.59056.3f, Department of Chemistry, , University of Calcutta, ; 92, APC Road, Kolkata, 700009 India
[3 ]ISNI 0000 0001 0075 5874, GRID grid.7892.4, Karlsruhe Institute of Technology (KIT), Institute of Organic Chemistry (IOC), ; Kaiserstraße 12, 76131 Karlsruhe, Germany
###### Article
10685
10.1038/s41467-019-10685-0
6599004
31253767

###### Funding
Funded by: European Research Council (ERC)
###### Categories
Article