The Dutch biotech company PamGene has developed a micro array platform for activity proteomics, which allows for functional characterization of proteins and modulation thereof by compounds. The target protein is repeatedly pumped through a porous solid phase with immobilized probes and enables diffusion-independent interaction kinetics resulting in short assay time and thus preservation of target protein integrity.
Using this approach, the activity of Nuclear Receptors (NRs), a family of ligand-activated transcription factors, is characterised through binding to a set of peptide probes representing a wide range of coregulator proteins. In vivo, the coregulators that are recruited by the NR at the target gen locus, modulate local chromatin structure thus regulate DNA accessibility for gene transcription by RNA polymerase. Differential (co)expression and utilisation of coregulators for cell types and genes play an important role in compound response.
Characterisation of compounds through the Micro array Assay for Real-time Coregulator-Nuclear receptor Interaction (MARCoNI) has been successfully applied in various drug development programs as well as identification and characterisation of toxic substances.
Within the in vitro WP2 of EDCMET, PamGene will subject a series of ED candidate chemicals to MARCoNI using a range of NRs. This screen will provide mechanistic data for the identification of compounds with a capability of canonical NR activity modulation. These data can be used to 1. generate or validate in silico models for target engagement and AOP (WP1), 2. bridge and validate in vitro assays (WP2) such as target binding and gene reporter assays and 3. functionally classify EDs for compound prioritisation and as a predictor for (differential) AOPs in general.
Rinie van Beuningen
VP Business Development
email: rvbeuningen (at) pamgene.com
tel. +31 73 615 80 80