Aragen in vitro pharmacology can facilitate lead identification and optimization of NCEs with end-to-end solutions in integrated drug discovery. These include target validation, optimization of biochemical, cellular and selectivity screens, the establishment of disease relevant secondary assays and the implementation of a biomarker strategy. Our development of disease relevant assays spans multiple therapeutic areas, including Oncology, Immuno-oncology, Inflammation, Autoimmune Disorders, Fibrosis, Cardiovascular and Metabolic Diseases. The identification, validation and screening of biomarkers is supported by diverse platforms such as qPCR, Luminex, flow cytometry, high-throughput Western blotting, high content imaging and LC-MS/MS. We are now a key player and partner to major companies in targeted protein degradation (TPD), executing complete workflows across reagent generation, assay development and screening of degraders. Additionally, we support top agrochemical organizations with screening for insecticidal, fungicidal and herbicidal site of action studies and hit identification. Our trademarked panel of in vitro toxicology assays (Toxvit) performed under GLP guidelines enables early go/no-go pipeline decisions.
Assay Development & Screening
Biochemical and cell-based assays employing recombinant proteins, normal and engineered cell lines and reporter cell systems can be performed for a wide range of biological target classes. Reagents for assay development and screening can either be commercially purchased or produced at our reagent generation laboratories. Liquid handling systems, multimode plate readers, multiplex, phenotypic, label-free and radiometric screening platforms provide wide support for high-throughput screening campaigns.
Targeted Protein Degradation
Proteolysis targeting chimera or PROTAC is a paradigm shifting novel drug discovery strategy providing significant opportunity to transform the way medicinal chemistry and discovery programs are planned and executed. With sub-stoichiometric catalytic mode of action, PROTAC reduces the need for target occupancy as necessitated with traditional small molecule inhibitors and is being actively explored for Oncology and Inflammatory Disorders.
Key assays to support degrader programs need to take into consideration the key aspects of ubiquitin proteasomal machinery and E3 ligases involved to make hetero-bifunctional degraders or molecular glues.
Binding assay: fluorescence polarization based competitive binding assay to evaluate binary binding affinity
Ternary complex formation assay: AlphaScreen®, AlphaLISA®, or TR-FRET based assay to determine the formation of ternary complex
Protein degradation assay: reporter complementation assays with customized stable cell lines to determine intracellular protein degradation in presence of degraders and DC50 and Dmax generation
Other Assays supporting the TPD Platform:
Evaluating the ubiquitination of target proteins
Western blot analysis of degradation of target protein
Competition assays using unconjugated recruitment motifs
Aragen develops custom solutions to help farmers safeguard their harvest. As a partner to top agrochemical companies for over 10 years, we have wide experience in agrochemical research. Our scientists have been supporting screening assays in insecticidal, fungicidal and herbicidal site of action studies. We provide end-to-end support in compound screening and hit identification. Our team has developed a diversity of assays to identify the compound site of action in insects and plants, including mitochondrial, cell membrane, amino acid related, neurotransmitter and photosystems I and II.
Crop Protection Support
Screening for Insecticidal Site of Action (ISOA)
Electron transport chain assay using mitochondria from insects and nematodes to confirm the site of action of complexes I, III and IV or II and III in respiratory disruptor classes
Oxidative phosphorylation assay using Sf9 cells: a cell-based assay using Sf9 cells to confirm the site of action of mitochondria complex V in respiratory disruptor classes
Acetylcholinesterase inhibition assay using insect source: an off-target assay to confirm neurotransmitter inhibition
Mitochondrial toxicity: a cell-based assay to confirm respiratory disruptor classes
Proliferation assay using Sf9 cells: a cell-based assay to confirm the mode of action involved in the control of insect growth and development
Screening for Fungicidal Site of Action (FSOA)
Electron transport chain assay using mitochondria from fungi to confirm the site of action of complexes I, III and IV or II and III in respiratory disruptor classes
Ergosterol biosynthesis inhibition (EBI) screen: a cell-based assay using various fungi to confirm the inhibition of biosynthesis pathway using absorbance and LCMS platform technology
Screening for Herbicidal Site of Action (HSOA)
Acetolactate synthase enzymatic assay (ALS): a biochemical assay to confirm amino acid inhibitors
Photosystem I & II assay using thylakoids prepared from leaf sample to confirm the herbicidal action in photosynthesis using OxygraphPlus
Carotenoid pathway analysis (CRTB) using micro algae: a cell based assay to confirm the site of action of the carotenoid pathway LC/DAD
HPPD assay: a complex assay to confirm the enzyme inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors
Protoporphyrinogen oxidase (PPO): an enzymatic assay to confirm the site of action of protoporphyrinogen oxidase (PPO) inhibitors
THL assay: a simple biochemical assay to identify reactive compounds by assessing their reaction with glutathione (GSH), thereby eliminating the possibility for mammalian toxicity
GMO Testing & Crop Breeding Support
Adventitious presence testing for BT cotton
qPCR technique developed and tested for: DOW281-24-236, 3006-210-23, MON531, MON15985, MON88913
Molecular marker analysis for crop breeding like SNPs
Copy number analysis
Marker assisted selection
In Vitro Toxicology – Toxvit
We offer a broad suite of reliable toxicity testing solutions to enable go/no-go pipeline decisions:
Modern toxicity testing technology
Large scale operations with high-throughput equipment
Reduced cost and testing times
More robust mechanistic data
Decisions on human relevant dose levels
Validated testing protocols
In Vitro Toxicity Solutions
Cell loss/death (fluorescent imaging)
Nuclear size and morphology (fluorescent imaging)
Cell membrane permeability (fluorescent imaging)
~50 different cell lines of human origin available for cytotoxicity testing
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