Identify potential liability issues in early stages of drug discovery

Toxicity and clinical safety are one of the leading causes of drug candidate failure in preclinical and clinical testing stage, and also the major reason for the withdrawal of approved drugs from the market. For example, hepatotoxicity and cardiotoxicity result in the most severe problems in drug development and are often the cause of drug withdrawals. To reduce attrition of drug candidates during clinical development, toxicology and risk assessment should be an integrated part of the early drug discovery process.

WuXi Biology offers comprehensive services at the target and cellular level to assess drug safety profiles in the discovery process. With our expertise and cutting-edge technologies, we will provide high quality and cost-effective data with fast turnaround. Applying these assays to your drug discovery and development programs will help to avoid costly late-stage failures.


Off-target Profiling

WuXi Biology Mini Safety Panel | WuXi Mini 44

A primary safety panel, which is designed to identify compounds with the highest risk because it contains targets associated with the most serious ADRs. This panel is recommended for use early in drug discovery stage for early hazard identification.

The 44 selected targets are recommended by four major pharmaceutical companies (Bowes J. et al. Nat Rev Drug Discov. 2012), including  24 GPCRs,  8 ion channels,  7 enzymes,  3 monoamine transporters and  2 nuclear hormone receptors.

GPCRs

Adenosine receptor
Adrenergic receptors
Alpha1A
Cannabinoid receptor
Cholecystokinin receptor
Dopamine receptors
Endothelin receptor
Histamine receptor
5-Hydroxytryptamine receptor
Muscarinic receptor
Opioid receptor
Vasopressin receptor

Channels

Ca2+Channel
K+Channel
Na+channel
Serotonin
Nicotinic
Glutamate

Transporters and NR

Transporter DAT / 5HTT / NET
Steroid Nuclear Receptors

Enzymes

Protein-Tyrosine Kinase -CTK
Phosphodiesterase
Cyclooxygenase
Monoamine & NRT Synthesis & Metabolism

WuXi Biology Second Safety Panel | WuXi Extra 54

A panel of additional 54 targets. This more extensive panel contains such targets that have the combination of either low-hit-rate/high-risk ADRs or high-hit-rate/ lower-risk ADRs. This panel is ideal for broad characterization of a limited number of compounds for lead selection, provides data to drive SAR for lead optimization.

The 54 selected targets include 26 GPCRs, 5 ion channels, 18 enzymes, 3 nuclear hormone receptors and 2 transmembrane targets.

GPCRs

5-Hydroxytryptamine receptor
Adenosine receptor
Adrenoceptor
Bradykinin receptor
Cholecystokinin receptor
Dopamine receptor
PGE2 receptor
Platelet-Activating Factor
Endothelin receptor
Histamine receptor
Muscarinic receptor
Tachykinin receptor
Vasopressin receptor

Channels

ATP-sensitive inward rectifier potassium channel
Cav1.2 (L-type) Rat Calcium Ion Channel
Glutamate ( Non-Selective) Rat Ion Channel

NR

Estrogen receptor
Peroxisome proliferator activated receptor gamma
Progesterone receptor

Transmembrane (Other)

Sigma receptor

Enzymes

Angiotensin converting enzyme
Cholinesterase
Serine/threonine-protein kinase
Serine protease
Monoamine oxidase
Histone Deacetylase
INSR Tyrosine kinase
Rho-associated protein kinase
Vascular Endothelial Growth Factor Receptor
Phosphodiesterase

WuXi Biology Full Panel | WuXi 98

The combination of WuXi Mini 44 and WuXi Extra 54.


In vitro Toxicity Profiling

Toxicity is the major cause of drug candidate failure in the preclinical and clinical development stages as well as the major reason for the withdrawal of approved drugs from the market. While a toxicity test has been traditionally completed in the preclinical phase, in vitro toxicity studies in the early drug discovery stages could significantly reduce failures at a later stage and prevent economic loss.

WuXi AppTec offers a panel of in vitro toxicity assays designed to identify compound toxicity in the early drug discovery stage. By utilizing cutting-edge technologies including conventional and automated patch clamp, high content screening (HCS), and NanoString profiling, we provide high-quality data quickly and cost-effectively. Applying these assays to your lead ID and optimization strategy helps to make a more thorough analysis of the severity and specificity of toxicity. Then BTO guide candidate compounds through the planning and execution of downstream in vivo toxicity and efficacy tests.

Cardiac Safety Assessment

  • Cardiac ion channel safety panel (CIPA compliant) with manual and automated patch-clamp: including hERG, hCav1.2, hNav1.5 (early and late), hKCNQ1/mink, hKv4.3/KChIP2.2, hKir2.1 channels
  • Human stem cell derived cardiomyocytes testing on MEA

Cytotoxicity

  • Cell viability Assay: CellTiter-Glo® (Promega) or HCS assay
  • Apoptosis assay
  • CellTox™ Green cytotoxicity assay (Promega)
  • ApoTox-Glo™ Triplex Assay (Promega)

Mitochondrial Toxicity

  • Mitochondrial Membrane Potential Assay
  • Mitochondrial Reactive Oxygen Species (ROS) Assay
  • MitoXpress® Xtra OCR Assay (HS method) (Luxcel)
  • MitoXpress® Cellular Energy Flux OCR/ECAR Assay from (Luxcel)
  • Glucose/Galactose Assay
  • Seahorse Cellular Mitochondrial Stress Assay
  • MitoBiogenesis Assay

Lipotoxicity

  • Phospholipidosis Assay
  • Steatosis Assay

Hepatotoxicity

  • 2D culture hepatotoxicity testing using HepG2 cells or human primary hepatotoxicity
  • 3D culture hepatotoxicity testing using human primary hepatotoxicity

Nephrotoxicity

  • Selected general cytotoxicity and mitochondrial toxicity assays listed above

Genotoxicity

  • Bacteria Reverse Mutation Assay (Ames Assay)
  • HCS In Vitro Micronucleus Assay

Neurotoxicity

  • Neurite Outgrowth Assay

Photo Toxicity

  • In vitro 3T3 NRU Phototoxicity test
hERG current recorded on QPatch, patch clamp, hiPSC-vCMs recording on MEA system
Fig 1. A hERG current recorded on QPatch, B hiPSC-vCMs recording on MEA system.
Mitochondrial membrane potential assay using HepG2 cells, FCCP, antimycin
Fig 2, Mitochondrial membrane potential assay using HepG2 cells.
Nephrotoxicity assay using HK-2 cells and paclitaxel, staurosporine controls, paclitaxel
Fig 3. Nephrotoxicity assay with HK-2 cells. 
In vitro 3T3 NRU neutral red uptake phototoxicity test using amiodarone and chlorpromazine controls
Fig 4. In vitro 3T3 NRU phototoxicity test