Compound Selection

Problem: Prioritizing a Lead Series

In pre-clinical drug development, a series of compounds is developed through lead optimization. Once a lead series has been established, one compound must be selected for first-in-human trials. Making this decision requires a wide range of information. Even though targeted toxicity data may exist, there is no information on the overall level of biochemical perturbation. Being able to see how a drug impacts the global biochemical profile can help prioritize leads.

Solution: Survey the Biochemical Landscape

Metabolon's comprehensive biochemical profiling service surveys the biochemical landscape. This global perspective provides insight into the relative effects of a series of drugs on the animal model. This insight can also lead to a better understanding of both the target and off-target effects.

Case Study: Protease Inhibitors

Objective
Examine a series of protease inhibitors to show the relative amount of biochemical perturbation.

Method
  1. HepG2 and adipocytes in cell culture (10% FCS) were treated with five protease inhibitors and a control.
  2. Metabolomic analysis was performed on each group.

Results
The figure below shows the global metabolomic profile (as Z-plots) for each compound and the control. Each dot represents a different biochemical and the deviation from the central tendency shows the extent of biochemical perturbation. The green shaded boxes of each panel highlight the biochemicals with significant fold changes. These changes were mapped to physiological differences seen in animal models. In this case, compound 1 was the most desirable since it showed the fewest metabolic changes.