30- Season 2 Recap and Integration (S2E15)

Welcome back, everyone. It's wild to think we're
already at the end of season two of our deep
dive into drug discovery. I mean, from picking
out those promising targets to digging through
like mountains of data to find those awesome
leads. It's been a crazy journey, hasn't it?
Remember way back when we started, like forever
ago, just going over all those potential targets,
trying to figure out which ones were, you know,
the real deal, the ones that were going to make
a difference. Yeah. Target selection. Super important
first step. It really sets the stage for everything
that comes after and. You know, it's way more
complicated than just pointing out a protein
and crossing your fingers. Well, for sure. We
saw how some targets, especially the ones involved
in stuff like multi -drug resistance, those are
just inherently harder to drug. Yeah, those tricky
ones. Yeah, exactly. Like trying to, I don't
know, hit a moving target, but it's also wearing
camouflage. Perfect analogy. But then on the
flip side, we saw how picking a target that's,
you know, biologically relevant, one that's addressing
a real need that's not being met that can really
pay off big time later on. Absolutely. And once
we had our target locked in, that's when the
real fun began, right? The hunt for those hits,
you know, the molecules that could actually bind
to our target and maybe even like change how
it works. Remember that feeling when we finally
found a compound that showed some real promise?
Oh, yeah, that was awesome. It was like a huge
victory after weeks of just like. going through
data, tweaking those molecular structures. But
then came the reality check, lead optimization.
It wasn't enough just to find something that
could hit the target. It also had to survive
that trip through the body, all those crazy metabolic
pathways. Yeah, that's where things got really
interesting. Remember when we went deep into
ADME? Absorption, distribution, metabolism, excretion.
Yeah. Exactly. We learned that making a drug
candidate super potent is only half the battle,
right? Because a potent drug, if it gets destroyed
by the liver before it can reach its target,
or if it hangs around in the body for too long
causing all sorts of side effects, it's basically
useless. Totally. That's when it really hit me
how even tiny little changes to a molecule can
make a huge difference in how it behaves in the
body. It's crazy how much complexity is packed
into something that seems so simple, like a drug
molecule just doing its thing in the body. Yeah.
It's a real testament to how amazing and intricate
biological systems are. Speaking of complexity,
remember those reactive metabolites? Those were
wild. Oh, yeah. They really highlighted how important
it is to understand not just the drug but also
what happens to it once it gets into the body.
That was a real eye -opener for me. It's like
fascinating and kind of scary at the same time
to think that even after you've optimized for
target binding and stability, a drug could still
fail because of what happens after it binds.
Yeah, exactly. Can you remind us again what makes
these reactive metabolites so tricky? Sure. So
most drug metabolites are pretty stable, you
know, they get excreted eventually. But some,
they can become pharmacologically active or even
toxic. And those are the ones that can cause
a whole bunch of problems, from mild side effects
to really serious stuff like liver damage. So
it's like you're playing this game of molecular
chess, right? Right. You've got to anticipate
how the body might change the drug and then plan
for all those potential problems. Exactly. Take
silicoxib, for instance, this popular Keo X2
inhibitor, right? Yeah. It initially seemed like
a great alternative to the traditional NSAIDs
because it had fewer of those nasty GI side effects.
But then it turned out that one of its metabolites
was reactive, and that could potentially lead
to, like, liver toxicity. Wow. Yeah. That silicoxib
example, it just goes to show how even what seems
like a small change to the structure can really
affect how a drug is metabolized and its safety
profile. It's a good reminder that drug discovery
isn't just about finding the right key for the
lock. Right. It's about making sure that key
doesn't accidentally unlock a bunch of other
doors that you don't want to open. That's a great
analogy. And this whole thing about reactive
metabolites and how they can impact things, it's
not just some theoretical thing. It directly
affects how we design and choose future drug
candidates. It's a key piece of the puzzle when
you're trying to make therapies that are not
only effective but also safe for people. Speaking
of safety and effectiveness, maybe it's time
to revisit some of the setbacks we had in season
two. Remember those drug candidates that looked
so promising at first, but then, you know, they
kind of stumbled during development. Yeah, for
sure. Those were some tough lessons. But, you
know, they were valuable, even though they were
disappointing at the time. Each one gave us important
insights that are going to help us as we move
into this even more complex world of preclinical
development. Absolutely. It's easy to get all
excited when you have a good lead. But, you know,
those setbacks, they remind us that drug development,
it's a marathon. It's not a sprint. Yeah. And
figuring out why things fail. That's just as
important as celebrating the wins. You're right.
Like they say, you learn more from your mistakes
than from your successes. But how do those past
failures, how do they actually help us succeed
in the future? Well, think about that candidate
that just couldn't stay stable. Remember how
we figured out that it was being metabolized
super fast by a specific enzyme in the liver?
Yeah, CYP3A4. Like the Pac -Man of enzymes just
chomping away at our poor drug candidate. Exactly.
And that failure, it taught us how important
it is to check for those metabolic problems early
on. Now we know, right? So we can design future
candidates and we can keep CYP3A4 in mind. Like
maybe we tweak the structure to avoid that metabolic
pathway or we find different ways to give the
drug that bypassed the liver altogether. So it's
like, you know, scoping out the enemy's moves
and then adjusting our game plan. But those early
failures, they also showed us how hard it is
to predict how a drug is going to behave in people.
Remember all those discussions about PKPD modeling?
Oh, yeah, definitely. PKPD modeling, trying to
figure out what a drug's gonna do in the human
body based on data from the lab, it's a super
important tool, but it's not perfect. Figuring
out how to connect those preclinical models with
the crazy complexity of human biology, that's
one of the biggest challenges we face. It's like
trying to predict the weather, but instead of
clouds and stuff, you're dealing with... You
know, those cytochrome P450s and ton of other
biological factors. Perfect analogy. And that's
exactly why preclinical development is so important.
It's all about reducing those unknowns as much
as we can, gathering solid data, refining those
models, and basically building a strong foundation
for those clinical trials. It's where we put
all those lessons we learned from those past
failures into action. OK, so we got this foundation
right. built on both the wins and the losses
from season two. So what's next? What kind of
preclinical craziness is waiting for us in season
three? Well, one really cool area is in vivo
models. You know, we've talked a lot about cells
and molecules, but now it's time to see how these
drug candidates do in a living breathing system.
Ah, yeah. Those lab mice and rats we always hear
about. They're the real testers, huh? But why
not just use humans right from the start? I know,
it sounds easier. But using animals first, it
lets us check for safety and make sure the drug
works in a controlled environment before we even
think about giving it to people. Plus, we can
study all sorts of things like drug interactions,
dosing, and long -term effects. Things that would
be, you know, ethically tricky and practically
impossible with human volunteers. That makes
sense. But I bet picking the right animal model
is super important. They're not exactly tiny
humans, are they? Exactly. Different species,
they can metabolize metabolize drugs in totally
different ways and that can make a huge difference
when we're trying to predict drug interactions.
For example, let's say we're studying a new drug
and we think it might mess with CYP3A, that enzyme
that plays a big role in drug metabolism. Okay,
I'm with you. We want to see if our new drug
messes with how CYP3A does its job. So we give
it to some lab animals along with another drug
that we know is metabolized by CYP3A. Right,
exactly. Now mitazolam, that's a drug we often
use in these studies. But in mice, mitazolam
isn't only metabolized by CYP3A. Another enzyme,
CYPTC, gets in on the action too. And that can
make it hard to figure out what's really going
on and to accurately predict how our new drug
might interact with CYP3A in humans. So it's
like trying to measure one ingredient in a cake,
but the recipe has a secret ingredient that messes
up your measurements. Super frustrating. For
sure. But the good news is we have other choices.
In mice, if we use triazolam instead of mitazolam,
we might get a clearer picture because its metabolism
depends more on CYP3A. Picking the right model
and the right probe drug can make all the difference
when we're trying to predict drug interactions
in humans. Wow, even picking the right animal
model is complicated. But I guess that's what
makes this preclinical phase so important. Gotta
get those details right before we even think
about human trial. Absolutely. And once we've
got our models figured out, we need the right
tools to analyze what's happening. That's where
those fancy analytical techniques come into play.
Oh yeah, those tongue twisters like LC -MSMS
and supercritical fluid chromatography. They
always sound so high -tech. They really are powerful
tools. They let us see the tiny details of drug
metabolism. LC -MSMS, for example. It's like
a molecular detective. It helps us find and measure
even the tiniest amounts of a drug and its metabolites
in biological samples. So it's not just about
seeing if the drug's there, but also about figuring
out... what has been changed into, and where
those metabolites ends up. Exactly. And by measuring
those specific metabolites, especially the ones
we know can cause problems, we can really understand
how a drug behaves in the body. Remember coelacoxib.
LC -MSMS would be perfect for tracking that reactive
metabolite, helping us see how toxic it might
be. It's amazing how these tools let us track
a drug's journey through the body, like following
his footprints at a molecular level. But you
mentioned another technique, supercritical fluid
chromatography. What's so special about that
one? Supercritical fluid chromatography that's
a bit more specialized. It's really useful for
analyzing compounds that don't like heat or don't
behave well in the usual liquid chromatography
methods. It's all about finding the right tool
for the job, and sometimes we have to get a little
creative. Okay, so we've got our models, our
high -tech tools. What else do we need to think
about? in this preclinical phase. Well, remember,
a drug's journey doesn't stop in the lab. We
have to think about how we're going to make it,
too. Scaling up from making tiny amounts in the
lab to producing large batches of a consistent
and stable drug product? That's a big deal. Oh,
right. Going from a few milligrams in a flask
to, like, kilograms in a factory. That's a big
jump. It is. And that's where polymorph screening
comes in. Polymorph screening. That's a new one.
What is that? So drug molecules, they can exist
in different crystal forms. We call them polymorphs.
It's like having the same building blocks, but
arranged in slightly different ways, creating
structures that look and act differently. So
even though it's the same molecule, different
polymorphs can act differently in the body. Exactly.
Some polymorphs might dissolve more easily, which
affects how well the drug is absorbed, while
others might be more stable during storage so
they last longer on the shelf. Polymorph screening
helps us find the best form for manufacturing,
making sure the drug works consistently and is
high quality. It's incredible how much detail
goes into every single step. We have to consider
the target, the molecule, its journey through
the body, the tools we use to study it, and even
how we make it on a large scale. It really shows
how complex drug discovery is and how important
it is for scientists from different fields to
work together. And with all this complexity,
we can't lose sight of the goal to improve people's
health. Yeah, it's mind blowing when you think
about all the work and expertise that goes into
making a new drug. But then you think about how
it could help people, you know, relieve suffering,
make lives better, and it makes it all seem worth
it. Definitely. And as we move on to season three,
I think it's important to keep in mind that everything
we do, every decision we make, it's all about
making a difference for patients in the end.
Absolutely. But before we jump headfirst into
preclinical development, let's take a minute
to appreciate the successes from season two.
How do those winds, those big scientific breakthroughs,
how do they help us moving forward? Remember
how much time we spent picking our initial targets,
that careful work we did, evaluating things like
biological significance, if it was even possible
to drug the target and whether there was a real
need for a drug for that target that sets us
up for success. You know, developing therapies
that actually work and are safe. It's like choosing
the right battlefield strategically. So we're
in a good position to win in the long run. I
like that analogy. And then there was hit identification
and all that work we did to optimize the lead
compounds. Remember those first hits, those were
like little sparks of hope. But they were just
the beginning, right? It was through all that
fine tuning and tweaking that we turned those
early compounds into real drug candidates. It's
medicinal chemistry at its best, you know, understanding
those subtle connections between a molecule structure
and what it does, and then using that knowledge
to design molecules that are not only potent,
but also safe and effective in a real biological
system. And now we've got those optimized lead
compounds and all this knowledge we've gained
from both the good and the bad stuff that happened.
We're ready for this next chapter. Season 3 is
going to be a wild ride as we explore preclinical
development. It is, but even though we try to
plan everything out and find that perfect formula
for success, we have to remember that drug discovery
is also about unexpected discoveries. Sometimes
the most valuable lessons come when things don't
go as planned, you know, when we stumble upon
something new or find a different way of doing
things. So even with all the planning and careful
experiments, we should always be ready for those
aha moments, those accidental discoveries. that
can really change the course of medical history.
Absolutely. It's that mix of solid science and
being open to new ideas that often leads to those
big breakthroughs. Who knows what amazing discoveries
are waiting for us in season three. I can't wait
to find out. And to everyone listening, thanks
for joining us on this incredible journey through
drug discovery. We're excited to have you with
us as we dive into the exciting and challenging
world of preclinical development in season three.