Phenotypic screening in Organ-on-a-Chip systems: a 1537 kinase inhibitor library screen on a 3D angiogenesis assay

Modern drug development increasingly requires comprehensive models that can be utilized in the earliest stages of compound and target discovery. Here we report a phenotypic screening exercise in a high-throughput Organ-on-a-Chip setup. We assessed the inhibitory effect of 1537 protein kinase inhibit...

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Bibliographic Details
Published in:Angiogenesis (London) 2024-02, Vol.27 (1), p.37-49
Main Authors: Soragni, Camilla, Queiroz, Karla, Ng, Chee Ping, Stok, Arthur, Olivier, Thomas, Tzagkaraki, Dora, Heijmans, Jeroen, Suijker, Johnny, de Ruiter, Sander P. M., Olczyk, Aleksandra, Bokkers, Marleen, Schavemaker, Frederik, Trietsch, Sebastian J., Lanz, Henriëtte L., Vulto, Paul, Joore, Jos
Format: Article
Language:English
Subjects:
Angiogenesis
Angiogenesis inhibitors
Antineoplastic Agents - therapeutic use
Biochips
Biomedical and Life Sciences
Biomedicine
Blood vessels
Cancer Research
Cardiology
Cell Biology
Drug development
Enzyme inhibitors
Humans
Inhibitors
Kinases
Microfluidics
Microphysiological Systems
Neovascularization, Pathologic - drug therapy
Oncology
Ophthalmology
Original Paper
Protein Kinase Inhibitors - pharmacology
Toxicity
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Summary:Modern drug development increasingly requires comprehensive models that can be utilized in the earliest stages of compound and target discovery. Here we report a phenotypic screening exercise in a high-throughput Organ-on-a-Chip setup. We assessed the inhibitory effect of 1537 protein kinase inhibitors in an angiogenesis assay. Over 4000 micro-vessels were grown under perfusion flow in microfluidic chips, exposed to a cocktail of pro-angiogenic factors and subsequently exposed to the respective kinase inhibitors. Efficacy of compounds was evaluated by reduced angiogenic sprouting, whereas reduced integrity of the main micro-vessel was taken as a measure for toxicity. The screen yielded 53 hits with high anti-angiogenicity and low toxicity, of which 44 were previously unassociated with angiogenic pathways. This study demonstrates that Organ-on-a-Chip models can be screened in high numbers to identify novel compounds and targets. This will ultimately reduce bias in early-stage drug development and increases probability to identify first in class compounds and targets for today’s intractable diseases.
ISSN:0969-6970
1573-7209
DOI:10.1007/s10456-023-09888-3