Drug Action

Problem: Understanding the Mechanism of Action

In developing a drug, one of the key requirements is understanding how the drug interacts with the disease-related target.  Traditionally, mechanism of action studies have involved detailed studies of select biochemicals.  More recently, transcriptomic and proteomic analysis have provided some insight, but these techniques do not provide a complete picture.

Solution: Pinpointing Target-Related Biochemical Changes

Metabolon's comprehensive biochemical profiling service analyzes a broad range of biochemicals, typically in plasma and urine.  The results, showing increased or decreased biochemical concentrations in response to drug treatment, provides insight to pinpoint the affected target.  In addition, this approach shows other targets which are affected, which may lead to insights on drug safety.

Case Study: MOA of an Early Stage Cancer Drug

Objective
The putative target of a cancer drug was NF-kB, a transcription factor.  A comprehensive biochemical of cell lines was conducted.

Methods
Multiple myeloma cell lines were exposed to DMSO or drug (single dose) over time.  Samples were taken at 6h, 13h, 24h, and 27h.  Metabolomic analysis was performed by Metabolon on all samples using GC/MS and LC/MS.

Results
The number of significantly altered biochemicals rose from 27 at 6h to 65 at 27h.  Significant changes to metabolites related to NAD metabolism pointed to the drug affecting enzymes within this pathway.  The figure below shows the altered biochemicals on a fold-change plot.  As can be seen, significant fold increases were seen with nictoinamide and NAD+ whereas significant decreases were seen with gamma-glutamylglutamine and gluatamine.

Subsequent studies showed the drug has low nanomolar inhibition of nicotinamide phophoribosyl transferase (NAMPRT), an enzyme involved in NAD+ biosynthesis.  These results significantly changed the clinical development of this compound.