Hi, this is Jim Wells again. I'm going to tell you about part two: from hit to pill.
Now, last time we left off, we had taken you up through the stages of these nine stages.
We'd taken you up from the target identification stage, to hit ID, and now we're at the hit to lead stage.
And the key thing about this stage
is that we want to identify compounds that don't just bind to the protein,
they actually work inside a cell. And they actually show selectivity in a cell.
And this is yet another elevated level
and gets us closer to what we want, which is a drug that's safe and efficacious in people.
The key aspect of hit to lead stage is an iterative process in which we
not only show that the compound works in a biochemical assay,
but we also demonstrate that it works effectively and selectively in a cell-based assay.
So, it can actually go through the cell membrane, reach the target inside the cell,
if it is an intracellular target,
and engage that protein in a cell-based assay.
So, in starting this process, the compounds start off with potencies
that are weaker than we would like.
As shown in this biochemical binding assay
what we're looking for is compounds that will make the medicinal chemistry
that will improve the potency of the hit compound at least a factor of ten,
ideally a factor of twenty, in the biochemical assay.
We'll also be looking for things that start off with, from the hit stage,
that have weak cellular potency, shown here,
but with medicinal chemistry that correlates with the biochemical potency above,
drives the cellular potency to be more potent in the cell.
And this is all toward, the goal here is to get potent compounds
that are cell active.
Now, we also look in this stage for several other important properties.
For instance, we don't want it to bind to other off-targets
that are related to it that may cause toxicity.
So, what we'd prefer is that the compounds have potency that are at least ten-fold weaker
to the closest related target.
We'll also be looking to see that there's chemical evidence that we can advance these compounds.
When we look at compound's structures,
you should see that there are compounds which both
affect the target and compounds which don't affect the target
that are fairly closely related
suggesting that they're binding to a single site.
Because one of the properties of a drug is that it bind to a single site
on the target protein.
We'd like to know the molecular target; Michelle mentioned
that you can start off these hit-finding expeditions
just looking for cellular activity.
In that case, we don't really know the target that's involved.
At this stage, we really would like to have a molecular understanding of what that
small molecule is engaging.
Lastly, and very importantly,
in this especially for formulations reasons,
we look to have compounds which have solubilities above a hundred micromolar.
And that's because we wish the compounds to be
soluble and dissolve well once they're administered to an animal.
Ok, having successfully passed this stage,
of a hit to lead stage,
we're now into this very important and pivotal stage,
called lead optimization.
This is where we're looking to see that compounds that we've created
can actually work in a whole animal, can reach the
protein target, through a cell, and through the circulatory system of the animal.
Ok, so I think at this stage it would be good to understand
what happens when you swallow a pill.
Here's our patient right here, going to take a pill,
there's the pills, they go down through the saliva
into the stomach, where they're
subjected to pH one, so they have to survive that.
They come out of the stomach and they go straight into the duodenum,
which is this arrow here, which you see goes straight into the intestines.
Now, the intestinal, the intestines have about
two hundred square meters of surface area to absorb.
That's about the size of a tennis court.
There's a lot of opportunity to absorb a drug,
but it has to have the right physical properties to get across that intestinal barrier
so it actually enters into the blood stream.
Once it does get across that, into the intestine,
and into the bloodstream, the first thing that is does is
it goes straight into the liver through the portal vein, here,
and then meets a series of very important obstacles.
They include a variety of enzymes that are in the liver that are meant to detoxify,
get rid of, these foreign small molecules.
So, they would be things like p450s, which oxidize the compound,
or hydrolases, protease, lipases, esterases,
that would be hydrolyzing compounds.
There would be glucaronidation enzymes and the like,
which tag them so that they can be rapidly excreted.
Of course, all of these things can reduce the potency and the availability of the drug
to have its effect in the peripheral tissues where it's probably got to act.
So, if really does, the drug has to get through this very important gauntlet here,
of the liver in order to go on from there, throughout the circulatory system
first into the right atrium, then into the lungs,
and then back through the lungs, into the left atrium,
and then through the arterial system all the way throughout the body.
So, understanding the pathway that a pill has to take
is actually very important in this drug discovery process
because even though a compound could be great in a biochemical assay or a cell based assay
if it doesn't work in this system over here
then it's not going to be a drug.
Ok, once, now understanding that
and having successfully passed the hit-to-lead stage we're now ready to do lead optimization.
And that again is an iterative process of chemistry and biology
paired together. But this time, at the animal level.
So, the very first thing that happens when you have compounds from the hit-to-lead stage
is that you'd want to determine how well do they survive in the body.
How long do they live in the body?
And to do this, you typically give either an injection of the compound
or feed an animal this compound
and then determine the PK of the compound
in other words, how well does that compound,
this is time along the x-axis here and amount of compound
that's in an animal along the y-axis
and as the compound is injected, you see that there's a rise
in compound levels as it reaches, as it goes into the circulatory system
and then it decays.
And this half-life and other parameters
are used to judge how well will that compound work in an animal
or how long it will last in an animal.
The next stage is called the pharmacodynamics part of this
and there we're actually looking to see how active is this compound
in an animal model.
This, I show here, is an example of a xenograph model for cancer.
This, for instance, is time along the x-axis and along the y-axis is tumor volume.
You can see if the animal is untreated with your drug,
your drug candidate, the tumor grows rapidly,
that's this blue line here,
and then, in the case of a compound that shows some efficacy,
if treated with the animal, treating the animal with that, you can see you can suppress the growth of the tumor.
That would be a good result.
Now, one would continue along this process
of lead optimization until one has gotten compounds
that show good PK and good animal efficacy
according to those guidelines that we discussed at the beginning of this lecture.
The notion of lead optimization is really one of
trying to push compounds from the vast amount, trying to identify compounds
from the vast chemical space that's out there.
We, through the hit-to-lead process, we've identified potent compounds,
both biochemically and in cell assay,
we use pharmacokinetics to identify those compounds that have both potency and good pharmacokinetics
so we take compounds within this area of the Venn
and then using our animal efficacy experiments, our PD or pharmacodynamic models,
we're really interested the compounds that are sitting right in this narrow area here.
So, it's this iterative process of testing these compounds
in pharmacokinetics, pharmacodynamics and cell and biochemical assays
that ultimately then identifies a compound that can be deemed a clinical candidate.
This would be a compound that would be ready for IND enabling studies
and hopefully on the pathway to being a drug.
So, the goals for an oral drug, then, after this process
again are that we're looking for compounds that can be dosed
once a day, at hopefully less than a hundred milligrams per day,
we want reasonable protein binding potency
and reasonable cell activity.
We want a decent half-life, so that it only has to be taken once a day
and we want good oral uptake
so that it can be taken orally.
Ok, all of this work I told you about,
this reminds me of this Greek myth of this character down here,
who you can see is exhausted
and that's how you feel once you get to the clinical candidacy stage.
You've just spent a lot of time, a lot of effort,
from target ID, hit ID, hit to lead and lead optimization,
you've just reached this plateau here and now you look up
and there's all of this stuff still to go
because that's the drug development stage that you need to get to to finally reach the nirvana.
So, now having worked all, done all the work in the drug discovery part,
which is basically this area from target ID to, through lead optimization
to identify a clinical candidate,
that typically takes somewhere around three to four years to go through that process.
There's still a whole lot of work to go on.
From IND enabling all the way through registration and FDA approval.
This process is an even, much more expensive and longer process,
about four to eight years to get through that process.
And it's worth considering what are the,
what are some of the reasons that compounds, we should this as a funnel,
because there's a lot of attrition that goes on in this process.
In fact, when a compound enters the clinic,
here in phase one, only one in ten compounds will actually make it to being a pill.
What are some of the reasons that they don't make it all the way to being a pill?
About a third of the reasons are due to lack of efficacy.
So, this is, when a compound shown to be efficacious in animals
and all of the target ID experiments that were done before,
this really reflects the fact that we didn't have a validated target
to begin with. That there's more going on with the biology than we thought
and it's sort of back to the drawing board
about what is actually driving that.
Other reasons for compound failure
is about a third of them die because of toxicity in humans.
These are things that we couldn't really model in animals
and so they wind up being disqualified as, they may have failed in phase one.
Other reasons for failure are pharmacokinetics,
they just don't have the right clearance
and the right properties to be a once a day or twice a day medication.
And, so they can fail for those reasons.
There's another, and much less likely failure,
which is due to commercialization reasons,
and this may be because the company just feels that the market size is not what they thought,
the drug is really not going to be worth developing further.
And so they will stop that.
There are many other reasons that might happen,
but these represent the lion's share of the kind of failures that happen in the clinic.
So, we really need to get much better at doing this.
We know that healthcare costs are spiraling out of control
and this represents something like fifty to twenty percent of the GNP
and new drugs and new therapeutics can really
spare us a lot of money in our economy if we're able to find new compounds that can ameliorate a disease.
Because it's much better to treat it early than to have to deal with the symptoms
and the ramifications after.
This also highlights the fact that we need to get to
prevention and cure, versus crisis and symptom,
which is the process that we're in now.
It's much cheaper to prevent and cure
than it is to manage a crisis or just simply manage the symptoms of disease.
Now, how are we doing in this process?
Well, there's something like twenty thousand gene targets,
meaning twenty thousand genes that encode for proteins;
if each of those were associated with a disease,
there's got to be a one to one correlation
but you could imagine that we should be able to find a lot more drugs
because currently there's only two hundred drug targets that are addressed.
And that means we're a long way from really
saturating the genome, or the proteome, as it were, with potential compounds
that can affect disease.
The other thing is that these days
we're only adding, the FDA, while it approves something like
thirty to forty new drugs a year,
we're only adding three to four new targets addressed per year.
That's because many of the drugs that are approved these days
are what are called "me too" drugs
that are second generation drugs that may have better pharmacokinetics,
less toxicity, but they're really addressing a brand new mechanism.
We truly need to address new mechanisms if we're going to affect
our healthcare.
So, in the last little bit here,
I wanted to tell you why I think drug discovery is so exciting
from a scientific point of view.
And I'm going to do this, these next few slides
with the example of Gleevec.
Gleevec's a new drug to treat CML,
and other cancers.
And this was discovered from some very careful
molecular biology and oncology studies
and genome wide association studies, that showed that this target,
the ABL kinase, gets hyper activated when its fused in patients with
CML because of this fusion with this protein BCR.
So, BCR-ABL, when they're fused together
at the gene level and then encoding a protein,
leads to this hyperactive protein kinase
that phosphorylates its substrates much more active than it should
and that drives cellular proliferation in chronic myeloginous lukemias.
Now, turns out that there's a, this is a kinase that binds ATP
and using high through put screening, a group at Novartis was able to identify compounds
that would actually displace ATP from BCR-ABL
and thereby inactivate the kinase
so it that it would no longer drive CML.
And this was a spectacular discovery,
one of the first really highly-targeted kinase inhibitors
that showed dramatic effects on this really life-threatening disease.
Another aspect of drug discovery that's so fascinating
is the fact that it allows us to understand how small molecules bind to their proteins of interest.
These are, they use weak forces to carry out this binding
reaction and it's those weak forces that if we understood them better,
we could really make better drugs, discover drugs more rationally,
and more completely.
And so, by looking at the structures of compounds bound,
to here, we're showing Gleevec bound to BCR-ABL,
in the spheres here,
we can begin to understand the hydrogen bonding interactions
between the drug, the ion dipole interactions between the drug and the protein and
hydrophobic interactions between the drug and the protein
and we can make analogues, chemical analogues, of these drugs and see how that affects potency,
so we can really understand the molecular details of how these contacts drive potency
and that way we can then understand how we can build better ones
because by seeing the values of certain interactions,
we can encode those into the small molecule to drive potency.
Another aspect that I find particularly fascinating
is that proteins themselves are quite dynamic.
They're moving in solution, their side chains are rotating on the surface of them.
This is our friend BCR-ABL and when this protein
binds its substrate, it undergoes conformational changes
and when it binds the drug Gleevec, it involves other conformational changes.
So, maybe if we could show this movie here,
you can see here, as the protein binds the substrate,
there in this green region,
you can see a conformational change.
And then when it binds Gleevec, there's a much larger conformational change that ensues.
These conformational changes are very important
in understanding how proteins bind small molecules
and how they can be controlled
because they are moving, dynamic objects that can be trapped
in different conformations and drugs allow us
a way of studying these kind of phenomena.
Now, another thing that's very exciting about drug discovery
is it allows one to have, a chemical biologist or biologist, to have tools
that can allow you to effect a biology in a cell in a very rapid and dose dependent manner.
Small molecules will act, often, on the timescale of seconds
to minutes, and this is much faster than
such probative technologies like knockout mice,
which take the development of a whole organism,
or siRNA, which typically takes 72 hours before you've had a complete knockdown
of the protein of interest.
Another aspect of drug discovery that's very exciting,
and this is for the pharmacologists,
is that it allows them tools to understand, to relate the physiological
effect of inhibiting or activating a particular target,
on the animal itself.
And in how that relates to the disease.
And so, this really goes, provides, important tools for pharmacologists
and has for years, for understanding
how particular biologies are regulating the phenotypes that we see in animals.
And lastly, it provides tools for geneticists and clinicians to relate
pharmacogenomics and epidemiology to disease.
As I mentioned, the ultimate target validation is a drug itself,
an approved drug that is shown to be effective in a particular disease
indeed validates that target, that this is important.
And additionally, by looking at responders and non-responding patients
and the difference in their genomes, we can begin to understand what other factors modulate
the disease itself and what makes them sensitive or resistant to certain compounds.
And finally, one of the things that's so great about drug discovery and development
is that it provides the fundamental basis for a healthier society.
Drugs have made a huge impact on our
health and will continue to do so.
We have a lot more to do in this area, as I've shown you,
and this is something that's, I think, is particularly exciting and worthwhile doing.
So, I'd like to thank you for listening to this presentation and see you later!