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Assays
are allosterically regulating the kinase per se. So I where GPCRs are on the market. But actually
would say allosterism at kinases is more normal as most of those drugs target a very small subset of
opposed to exceptional. Whereas allosterism with GPCRs. There are a lot of GPCRs for which there
GPCRs is starting to become better understood. aren’t targets, I’m sorry, for which there aren’t
drugs. Is that because the assays are not picking
Arthur Christopoulos: I think allosterism is the anything up or, as Richard said, because we’re just
norm with just about everything. looking under the lamppost? I think we need to be
looking for assays that can appreciate whether
Martin Valler: But we shouldn’t forget the reason you have signalling through different G-proteins,
why GPCRs are good targets is because although signalling through beta arrestin, signalling when
they may have multifunctional responsibilities you modify with other co-factors, such as another
within the cell and downstream, upstream the lig- GPCR. And I think GPCRs shouldn’t be put up on
ands are very specific, and can be defined pretty a pedestal. At the end of the day, they’re proteins.
much in advance. The best thing of course is the So if you have an interaction between proteins,
target is on the outside of the cell, so we don’t need they will change each other’s confirmation. So
cell penetration for the drugs. And that is an over- when you’re looking for ligand binding interac-
riding benefit. So that is the key thing singling out tion, whenever you have an interaction at the
GPCRs as a promising class of targets. intracellular surface, they will be changing confir-
mation of the receptor. So assays that are for
Richard Eglen: I just want to say, are all of the example based on promiscuous G-proteins, you’ll
functional assays, the cell-based assays, are they be pulling out ligands that are specific for a
surrogates to investigating the ligand binding to promiscuous G-protein stabilised receptor because
the receptor, in terms of discovering drugs? Or are the G-protein actually does affect the confirma-
there other avenues for discovering new drugs that tion of the receptor. So you will be pulling out a
GPCRs act on other parts of the GPCR-mobilised subset of ligands, if you’re looking specifically for
pathway? In other words, if you could really meas- ligands that are going to certain G-proteins you
ure ligand binding, at the biomolecular event, is might miss them. If they’re specifically going to
that really what you’re looking for? Or are now arrestins you might miss them. And the other
people looking for drugs that act at the GPCR point as well is that a lot of the drugs – the prob-
driven pathway? lem with drugs – is not finding the compounds, it’s
finding compounds that don’t have side effects. So
David Marks: I don’t think there are a lot of peo- if we’re looking for selective compounds that
ple actually targetting the GPCR pathway itself, don’t have side effects, perhaps we need to identi-
because you may lose specificity there. Because the fy specific coupling partners and exclude others?
pathway proteins, when you look at them, are the Maybe we need to be looking at drugs that actu-
same. While the area where that’s different is the ally couple to multiple partners, but exclude a sub-
receptor itself. So that’s where you can have selec- set. Maybe you have two pathways that are good
tivity. Once you go past the receptor, it is difficult and one’s bad, so you exclude the one that’s bad?
to find selectivity. We need to be a little bit cleverer about how we
actually measure these endpoints. And perhaps we
Richard Eglen: I was wondering about the protein- need to be doing multiple endpoints.
protein interface, the arrestin interface, dimerase
interfaces... David Marks: But the issue is really do we know
what is the relevant receptor confirmation or
Robert Jordan: Well that’s a good question, receptor complex that we should be using for any
because one of the questions I was going to ask is particular disease phenotype that we want to treat?
on the dimer side. I wanted to ask whether any of
you have enabled or planned to enable GPCR Arthur Christopoulos: In most cases the answer
dimer assays? And do you think they will be the is no.
source of the next generation of targets?
David Marks: Right, if that’s the case, there’s
Kevin Pfleger: Yes, I think that dimerisation and nothing that can be done to try to take that
allosterism are the two main thrusts where the approach. So first we have to have a much better
field is going to be going to. I think that as has understanding of whether dimers, or heterodimers
been said here, yes we can look at a lot of drugs of receptors really have physiological relevance in
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