16- Selecting the Right Drug Target (S2E1)

All right, get ready for this one. Our deep dive
today takes us deep into how scientists choose
what to target with a new drug. You know, it's
really interesting. Like the foundation of how
that drug is going to work. Yeah. And it turns
out it's not just about finding something involved
in a disease. Right. There's a whole lot more
to think about. OK. It's this whole complex kind
of a dance between the science, the practicality.
Right. a whole bunch of criteria to consider.
So this is a pretty deep stack of research here.
It is. You ready to unpack it? Absolutely. I'm
already fascinated by this idea of like drugability.
Yeah. Is it kind of like a molecule can be super
important in the disease. Yeah. But if we can't
actually design a drug to effectively interact
with it. Right. It's a no -go. Exactly. That's
a great way to put it. OK. And think of it like
a lock and key. Some locks are just way too complex
for a key to fit properly. Drugability refers
to how feasible it is to design a drug that can
bind to a target and have the effect you want.
So it's going to have a good binding site. Yes.
Like a welcome mat for the drug. Exactly. We
need that drug to accurately hit its mark without
sort of going astray and causing these unintended
effects in other places in the body. like off
-target effects. Kind of like accidentally hitting
the wrong button on a control panel and causing
this whole cascade of unanticipated consequences.
Yeah, exactly. So on top of being druggable,
a good target needs to really minimize the risk.
of those off -target effects. And that's where
this really deep understanding of the target's
interactions all throughout the body becomes
really important. So it's like this balancing
act between effectiveness and safety. All of
this is happening before a drug even makes it
to market, right? Absolutely. And there's also
this question of market needs, you know? Right.
Will there be enough people who need a drug that
targets this particular molecule? Right. So a
target can be amazing scientifically, but if
there's no market for it, that might not get
developed. I mean, that's kind of a sobering
thought, right? Yeah. Speaking of successful
targets, though. Yes. There's a good example
in one of these articles, HER2. Right. A protein
involved in certain cancers. Yes, HGR2. This
has been a game changer in cancer treatment.
OK. It's a really good example of how choosing
the right target can totally revolutionize how
we treat patients. OK, so tell me about HGR2.
So it turns out that some drugs, even when they're
metabolized really fast by the body. Right. can
still be really effective against HGR2. It's
like they hit their target really quickly and
powerfully even if they don't stick around for
very long. So it's not always a bad thing if
a drug breaks down rapidly? Exactly. It just
shows that sometimes what we might think of as
a limitation can actually be an advantage. That's
what makes drug development so fascinating. There's
always new things to discover. Always surprises
around the corner. So science is all about challenging
those assumptions and looking for those unexpected
solutions. I love that. Yeah, absolutely. But
speaking of unexpected, you know, not all these
drug target stories have happy endings. There
are tons of targets that seemed really promising,
but they just flopped in clinical trials. You
know, the research mentioned these undruggable
proteins, which kind of sounds like a scientific
heartbreak to me. Yeah, it is in a way. So much
potential, but just... out of reach. What makes
a protein undruggable? Okay, imagine trying to
grab a really smooth ball. Okay, like there's
nowhere to get a good grip, right? Yeah, so some
proteins are kind of like that. They just don't
have those very clear defined Binding sites that
we need. Okay to design a drug to effectively
bind So it's more than just you know, the target
being present, right? It's gonna have the right
structure and accessibility. Yes, exactly It's
like you need to find the right keyhole, right,
you know, not just have a key Thankfully though
science doesn't give up easily. Yeah researchers
are constantly working on new strategies to try
to tackle these really challenging targets. And
one exciting area is something called molecular
glue. Molecular glue, that sounds cool. Yeah,
it is. How do they work? All right, so think
of it this way. Sometimes you have two proteins,
and they need to interact for a specific process
to happen in the body, but they just can't quite
get it together. So a molecular glue kind of
acts like a matchmaker. It binds to both of those
proteins, brings them really close together,
and helps them to interact. Oh, so it creates
the right conditions for a molecular tango. Yeah,
precisely. I like that. And this is a game changer
for those undruggable proteins, because molecular
glues don't need those traditional binding sites.
It's like a completely new way of thinking about
targeting drugs. It really opens up a... all
kinds of possibilities. Yeah. It is. Yeah. Yeah.
And speaking of new approaches, there's another
one I think you'll find pretty fascinating too.
All right. Lay it on me. It's called targeted
protein degradation. Targeted protein degradation.
OK. I've heard of this. Yeah. It sounds almost
like taking out the trash. That's a great way
to put it. OK. So instead of just blocking a
protein's function. Right. This approach actually
gets rid of the protein entirely. Like a demolition
crew for those problem proteins. Yeah. Exactly.
So how does this molecular cleanup crew actually
work? Well, it actually uses the cell's own waste
disposal system. Oh, yeah. You can think about
it like tagging a piece of furniture for a bulk
pickup. Right. So this approach basically attaches
a tag to that protein we want to get rid of,
marking it for destruction by the cell's internal
machinery. So we're not actually putting anything
foreign into the cell. We're just kind of manipulating
the cell's natural processes. Yeah. That's pretty
elegant. Yeah. It is. It has huge potential for
treating all sorts of diseases. Wow. But of course,
as with any new technology, you know, there are
challenges. Sure. We need to be sure that these
systems are super specific. Right. And don't
accidentally take out proteins that we need for
normal, healthy cells. Like, make sure the demolition
crew doesn't knock down the wrong building. You
got it. Precision is key. Absolutely. But that's
the exciting thing about science. Yeah. It's
this constant journey, right? It is. Refining
and improving. Always. You know, you mentioned
another cutting edge approach a little earlier.
Oh, yeah. Protax. Yes, Protax. What can you tell
me about those? Well, I know they're another
example of this targeted protein degradation
that we were talking about. Right. And they sound
kind of like tiny assassins. Yeah. With this
one very specific mission. That's a great way
to think about it. So. Essentially, a protac
molecule has these two binding sites. One binds
to the protein that we want to eliminate. The
other binds to a component of the cell's protein
degradation machinery. So it's kind of like a
bridge, connecting the target to the cellular
garbage disposal. Exactly. And once that connection
is made, that target protein gets tagged for
destruction and the cell's proteasome comes along
and just ranked it down. So it's kind of like
a sophisticated game of molecular tag. Yeah.
with the pro -tac sort of directing the action.
I love that analogy. And it seems like this approach
could really be a game changer for those undruggable
proteins. Yeah, for sure. It opens up this whole
new way to target proteins that were previously
unreachable, right? Exactly. Plus it has the
potential to be a lot more selective. Yes. So
we can be more precise about which proteins we
eliminate, right? Right. Minimize those off -target
effects. Exactly. It's not just about hitting
a target. It's about hitting it in a really controlled...
precise way. So like it's like the difference
between using a sledgehammer and a scalpel. the
perfect analogy. But of course, you know, designing
effective pro -otacs, it's still a very challenging
task. We need to make sure they bind to the right
targets. Uh -huh. Make sure that they're stable
enough to reach their destination. Inside the
cell. Yes. But the potential is huge. Huge, yeah.
So it's really exciting to see how this is all
going to evolve. Yeah. And it all kind of comes
back to this question that we started with. Yeah.
How do we choose the right target for a drug?
That is the question. It drives so much innovation
in medicine. Absolutely. And as we get these
even more sophisticated techniques. Like pro
-tax. Like pro -tax. Molecular glues. It really
raises even more interesting questions about
the future of drug development, doesn't it? It
does, yeah. What kind of questions are you thinking
of? Well, you know, we've focused a lot on these
individual proteins as targets. But what if we
could start thinking bigger? OK, like where you're
going with this. What if, in the future, we could
target entire networks of interacting molecules?
Wow, yeah. Instead of just one protein. It's
kind of like shifting from a single player to
a whole team sport. Right. Exactly. Or what if
we could go even further? OK. And target the
cellular environment itself. Oh, wow. You know,
create conditions that are just not favorable
for disease. Yeah. Almost like terraforming.
Right. but on this microscopic level. Exactly.
I mean, it just opens up so many possibilities.
It does, yeah. And it just shows how much we
still have to learn and explore in this field,
you know? And it's all really driven by human
curiosity, right? Yes. And this desire to just...
alleviate suffering. Absolutely. It's pretty
awe -inspiring to think about all that potential.
It is, yeah. It also kind of emphasizes, though,
how complex these systems are that we're dealing
with. Right. Even when you're just targeting
a single protein, there's always a chance, right,
of unintended consequences. We talked about off
-target effects earlier. Right. But what about,
like, how a drug designed to work in one part
of the body might have effects somewhere else?
That is a really crucial point, yeah. You're
talking about selectivity, which is... a huge
challenge in drug development. The ideal drug,
it would be like a laser beam just hitting its
target. No collateral damage. Exactly. No collateral
damage. But in reality, it's really tough to
achieve that level of precision, especially because
the body is all these interconnected systems.
It's not just like a bunch of separate compartments.
No, it's not. Right. Everything affects everything
else. Yeah. Like that butterfly effect thing.
Yeah. Even tiny little changes can lead to these
big unpredictable outcomes. Totally. And then
on top of that, you have to consider how the
drug is metabolized in the body, right? Oh, right.
So it might be designed to interact with this
one specific target, but then it breaks down
into all these different forms, metabolites,
and those could have their own unintended interactions.
So it's like trying to predict the moves of a
chess grandmaster. Yes. You can maybe anticipate
the first few moves, but then the game just takes
on a life of its own. Totally. That's a great
analogy. And that's exactly why all this preclinical
testing is so important. Researchers use all
these different techniques, computer simulations,
experiments with cells, animals, trying to figure
out how that drug is going to behave in the body.
and what the potential for off -target effects
might be. So it's a constant process of just
refinement. It is. Always learning new things.
Always. It really is humbling though, right?
It is. Even with all these incredible advances
that we've made, we're still kind of grappling
with the complexity of biology. Absolutely. Speaking
of advances though, I read an article recently
about the role of artificial intelligence in
drug development. It sounds like AI could really
change the game. In what way? In helping us choose
the right targets and design better drugs. So
AI is revolutionizing a lot of different aspects
of drug development. Absolutely. It's like having
this super powered research assistant that can
analyze all this data, identify patterns, make
predictions. So it's not about replacing scientists,
but more like giving them this really powerful
tool. Yeah, exactly. Giving them this amazing
tool to sift through all this data that's generated
by research today. So it's kind of like this
high -tum detective. Yeah, I like that. Helping
us crack the case, so to speak, of disease by
finding these clues hidden in our DNA. It is.
And AI can actually go even further than that,
too. It can analyze the 3D structures of proteins
and predict which ones are likely to be... So
back to the lock and key. Exactly. Back to the
lock and key. That can save researchers so much
time. Yeah, tons of trial and error potentially.
Exactly. It's really incredible to think about
the potential for AI to accelerate that pace
of discovery. I know, it is. But I imagine there
are still limitations, right? Oh, for sure. Ethical
considerations with using AI? Of course, of course.
AI is a really powerful tool, but it's only as
good as the data that it's trained on. And we
have to remember that AI algorithms can reflect
the biases of their creators. So it's really
important to be aware of those potential ethical
implications. At the end of the day, AI is a
tool. And it needs to be used responsibly and
always in conjunction with human expertise. Just
more of a partnership. Yeah, it is. AI assisting
and enhancing that human ingenuity. Exactly.
Well, we've covered so much today. I know we
have. From those basic principles of drug target
selection to AI molecular glues. Right, targeted
protein degradation. Yeah, it's like we've taken
this journey through the past, present, and future
of drug development. It really feels that way.
And what's so amazing is how far we've come,
but also how much more we still have to figure
out. It's this constantly evolving field, right?
It is. Driven by our curiosity, desire to reduce
suffering. Absolutely. You know, it is inspiring
to think about the work of all these researchers.
It is, yeah. All around the world. Yeah. Pushing
the boundaries of what's possible. It is. I think
I have one final thought to leave our listeners
with. Okay, I'd love to hear it. The future of
drug development. Yeah. Might not be just about
targeting those individual proteins. Uh -huh.
But actually about targeting... entire networks
of interacting molecules. Yeah. Or even as we
talked about the cellular environment itself.
Yes. That's going to be a challenge that requires
so much ingenuity. Absolutely. Collaboration
and this real willingness to embrace these new
ways of thinking. Yeah, I agree. And I have no
doubt scientists will rise to the challenge.
I agree. I think so too. Well, thank you for
joining us on this deep dive today into the world
of drug development. My pleasure. We hope you've
enjoyed it. I did. And we'll see you next time.
Sounds good. It really opens up a whole world
of possibilities. And speaking of new approaches,
there's another one I think you'll find pretty
fascinating, too. All right, lay it on me. It's
called targeted protein degradation. Targeted
protein degradation. OK. OK, I've heard of this.
It sounds almost like taking out the trash. That's
a great way to put it. So instead of just blocking
a protein's function, this approach actually
gets rid of the protein entirely. Like a demolition
crew for those problem proteins. Yes, exactly.
So how does this molecular cleanup crew actually
work? Well, it actually uses the cell's own waste
disposal system. You can think about it like
tagging a piece of furniture for a bulk pickup.
So this approach basically attaches a tag to
that protein we want to get rid of, marking it
for destruction by the cell's internal machinery.
So we're not actually putting anything foreign
into the cell. We're just kind of manipulating
the cell's natural processes. That's pretty elegant.
Yeah, it has huge potential for treating all
sorts of diseases. But of course, as with any
new technology, You know there are challenges.
Sure. We need to be sure that these systems are
super specific. Right. And don't accidentally
take out proteins that we need for normal healthy
cells. Like make sure the demolition crew doesn't
knock down the wrong building. You've got precision
is key. Absolutely. But that's the exciting thing
about science. Yeah. It's this constant journey,
right? Refining and improving. Always. You mentioned
another cutting edge approach a little earlier,
protax. Yes, protax. What can you tell me about
those? Well, I know they are another example
of this targeted protein degradation that we
were talking about. And they sound kind of like
tiny assassins. Yeah. With this one very specific
mission. That's a great way to think about it.
So essentially, a protax molecule has these two
binding sites. Okay. One binds to the protein
that we want to eliminate. The other binds to
a component of the cell's protein degradation
machinery. So it's kind of like a bridge. Yes.
Connecting the target to the cellular garbage
disposal. Exactly, and once that connection is
made, that target protein gets tagged for destruction
and the cell's proteasome comes along and just
breaks it down. So it's kind of like this sophisticated
game of molecular tag with the protax sort of
directing the action. I love that analogy, and
it seems like this approach could really be a
game changer for those undruggable proteins.
Yeah, for sure. It opens up this whole new way
to target proteins that were previously unreachable.
Yeah, exactly. Plus it has the potential to be
a lot more selective. Yes. So we can be more
precise about which proteins we eliminate, right?
Right. Minimize those off -target effects. Exactly.
It's not just about hitting a target. It's about
hitting it in a really controlled, precise way.
So it's like the difference between using a sledgehammer
and a scalpel. The perfect analogy, but of course,
you know, designing effective pro -attacks, it's
still a very challenging task. We need to make
sure they bind to the right targets, make sure
that they're stable enough to reach their destination.
Inside the cell. Yes. But the potential is huge.
So it's really exciting to see how this is all
going to evolve. And it all kind of comes back
to this question that we started with. How do
we choose the right target for a drug? That is
the question. It drives so much innovation in
medicine. Absolutely. And as we get these even
more sophisticated techniques... Like pro -tacs.
Right, pro -tacs. It really raises even more
interesting questions about the future of drug
development, doesn't it? It does, yeah. What
kind of questions are you thinking of? Well,
you know, we focus a lot on these individual
proteins as targets. But what if we could start
thinking bigger? Okay, I like where you're going
with this. What if in the future we could target
you know, entire networks of interacting molecules.
Wow. Instead of just one protein. Yeah. It's
kind of like shifting from a single player to
a whole team sport. Exactly. Or what if we could
go even further and target the cellular environment
itself? You know, create conditions that are
just not favorable for disease. Yeah. Almost
like terraforming, but on this microscopic level.
Exactly. I mean, it just opens up so many possibilities.
It does. Yeah. And it just shows how much we
still have to learn and explore in this. field,
you know? And it's all really driven by human
curiosity, right? Yes. And this desire to just
alleviate suffering. Absolutely. Yeah, it is
pretty awe -inspiring to think about all that
potential, but it also kind of underscores how
complex these systems are that we're dealing
with. Even when you're targeting just a single
protein, there's always a chance of unintended
consequences. We talked about off -target effects,
but what about a drug that's designed to work
in one part of the body? but then it ends up
having effects somewhere else. Yeah, that's a
really crucial point. You're talking about selectivity,
which is a huge challenge in drug development.
The ideal drug, it would be like a laser beam,
just hitting its target with no collateral damage.
Right, no collateral, but in reality. Yeah. It's
really hard to get that level of precision. Yeah,
it is. Especially because the body is not just
these separate compartments. Right. It's all
interconnected. Right. Everything affects everything
else. It's like that butterfly effect idea. Even
small changes can have these big, unpredictable
outcomes. Absolutely. And then on top of that,
you have to think about how the drug is metabolized
in the body. Oh, right. So it might be designed
to interact with one specific target. Yeah. But
then it breaks down into all these different
forms, metabolites. Right, metabolites. And those
could have their own unintended interactions.
So it's like you're trying to predict what a
chess grandmaster is going to do. Yeah. You might
know the first couple of moves. But then the
game just kind of takes on a life of its own.
Totally. That's a great analogy. And that's why
this preclinical testing is so important. Right.
Researchers use all these different techniques,
like computer simulations, experiments with cells
and animals. Right. Trying to figure out, OK,
how is this drug going to actually behave in
the body? What's the potential for off -target
effects? Right. So it's just this constant process
of refinement. Yeah. Always learning new things.
Always learning. Always. It is humbling, though,
right? It is. with all the advances we've made,
we're still grappling with how complex biology
is. Absolutely. Speaking of advances though,
one of the articles that I read was talking about
the role of artificial intelligence in drug development.
Oh, interesting. It sounds like AI could be a
real game changer. Yeah. How so? You know, helping
us choose the right targets and design better
drugs. So artificial intelligence is... revolutionizing
drug development in a lot of ways. Totally. It's
like having this super -powered research assistant
that can analyze tons of data, identify patterns,
and make predictions. So it's not about replacing
human scientists. No. It's about giving them
a really powerful tool. Exactly. Augmenting their
abilities, helping them sift through the mountains
of data. It's like a high -tech detective helping
us crack the case of disease. I like that a lot,
yeah. uncovering those hidden clues in our DNA.
Totally. And AI can even go further. Really?
It can analyze the three -dimensional structures
of proteins and predict which ones are going
to be drugable. Oh, wow. So back to that lock
and key idea. Exactly. Back to the lock and key.
That could save researchers so much time and
effort. Tons of time and effort, yeah. It's incredible
to think about how AI could really accelerate
that pace of discovery. I know. It's so exciting.
But you know, there are limitations and ethical
considerations to think about. AI is a powerful
tool, but it's only as good as the data. that
it's trained on. Right. And we have to remember
that those algorithms can reflect the biases
of the people who created them. Right. So it's
really important to think about the potential
ethical implications. It's a tool that needs
to be used responsibly. Absolutely. And always
together with human expertise. Yeah, it's a partnership.
Right. AI assisting and enhancing human ingenuity.
Exactly. Well, we've covered a lot of ground
today. From the basics of drug target selection,
all the way to the potential of AI molecular
glues. Targeted protein degradation. Yeah, it
feels like we've taken this journey through the
past, present, and future of drug development.
It really does. Amazing how far we've come, but
also how much more there is to learn. It's a
field that's constantly evolving. That's constantly
evolving. Driven by human curiosity and the desire
to reduce suffering. It is so inspiring to think
about all the researchers around the world. It
is. Who are pushing the boundaries of what's
possible. I think this is a good place to wrap
up. Yeah. So thank you for joining us today on
this deep dive into the world of drug development.
It was my pleasure. We hope you enjoyed it. I
did. And we'll see you next time. Sounds great.