1. Academic Validation
  2. Phenotypic screening in Organ-on-a-Chip systems: a 1537 kinase inhibitor library screen on a 3D angiogenesis assay

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

  • Angiogenesis. 2023 Jul 26. doi: 10.1007/s10456-023-09888-3.
Camilla Soragni # 1 2 Karla Queiroz # 1 Chee Ping Ng # 1 Arthur Stok 1 Thomas Olivier 1 Dora Tzagkaraki 1 Jeroen Heijmans 1 Johnny Suijker 1 Sander P M de Ruiter 1 Aleksandra Olczyk 1 Marleen Bokkers 1 Frederik Schavemaker 1 Sebastian J Trietsch 1 Henriëtte L Lanz 1 Paul Vulto 1 Jos Joore 3
Affiliations

Affiliations

  • 1 MIMETAS BV, De Limes 7, 2342 DH, Oegstgeest, The Netherlands.
  • 2 Department of Cardiology, Maastricht University, Maastricht, The Netherlands.
  • 3 MIMETAS BV, De Limes 7, 2342 DH, Oegstgeest, The Netherlands. j.joore@mimetas.com.
  • # Contributed equally.
Abstract

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.

Keywords

Angiogenesis; High throughput screening; Microphysiological systems; Organ-on-a-Chip; Phenotypic screening; Protein kinase inhibitors.

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