Genetic or genomic approaches are used to validate targets of potential therapeutic interest. Find out how genomic approaches are used in identifying GPCR targets.
Drug Discovery & Development magazine conducted a roundtable discussion with industry scientists to answer questions about GPCR. Below are the answers to a question related to genomic or genetic approaches to identify GPCR targets. To review the full discussion, see all related articles.
James Netterwald: One approach that I haven’t heard mentioned is a genetic or genomic approach to either identifying GPCR targets or validating the targets in some way. Are any of you utilizing a genomic or –omic technology in your GPCR work?
Suresh Poda: Yes, we do our initial target identification with genomic approaches. Most of the time, a lot of people have used GPCR animal knockout models to study physiology and the phenotypes. There are some recent trends in this area, knocking out the target in a particular tissue in which you are most interested. These tools are really useful at the target identification stage. It’s also important to test this hypothesis using small drug-like molecules.
Charles Lunn: Genetic approaches are used to validate targets of potential therapeutic interest… If a particular receptor is of interest you genetically delete it, then test whether the resulting animal has a phenotype consistent with your model. Your results may suggest whether your therapeutic compound should be an agonist for the target receptor, or an antagonist. You can then target your screening paradigm to select compounds with the desired pharmacology. It is a widely used technique.
Richard Eglen: I think another side to that point, which may be less active than it was four or five years ago, was the deorphanization of those GPCRs … where there were many programs where orphan GPCRs—one that was from a sequence that was a novel GPCR, was characterized, and had no identified endogenous ligands—and that was advanced as a potential disease target. Clearly a lot of this was done at risk since if one didn’t know the endogenous ligand, then one wasn’t too sure whether it was involved in a disease in the first place. But my perception of this is that deorphanization in drug discovery around GPCRs tends to be less an activity than maybe it was. But certainly, genomic approaches were used to identify a whole range of novel GPCRs and how they may relate to pathophysiology.
Lunn: Part of the problem with GPCR deorphanization was that it is really hard. Such research takes a lot of time and effort from a large group of skilled investigators. Plus, successes are few—the easy receptors have already been deorphanized. It comes down to a business decision. Do you want to invest a significant part of your research dollar to seek a rare event, or rather wait until academics—who have a little more flexibility to pursue these programs—to identify a target. A decision about the therapeutic value of the target can then be determined.
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