thank you very much today I’m going to tell you a story about cancer drug
tell you a story about cancer drug
tell you a story about cancer drug discovery and about trying to build
discovery and about trying to build
discovery and about trying to build molecules that target proteins that
molecules that target proteins that
molecules that target proteins that drive the human cancer and the protein
drive the human cancer and the protein
drive the human cancer and the protein that I’m going to talk about today is
that I’m going to talk about today is
that I’m going to talk about today is called signal transducer an activator of
called signal transducer an activator of
called signal transducer an activator of transcription 3 protein and it’s shown
transcription 3 protein and it’s shown
transcription 3 protein and it’s shown here now I didn’t always do cancer
here now I didn’t always do cancer
here now I didn’t always do cancer research in fact when I started I was a
research in fact when I started I was a
research in fact when I started I was a synthetic organic chemist and I’ll just
synthetic organic chemist and I’ll just
synthetic organic chemist and I’ll just give you a little bio and I started
give you a little bio and I started
give you a little bio and I started making molecules really to make the
making molecules really to make the
making molecules really to make the hardest molecule that I could and for me
hardest molecule that I could and for me
hardest molecule that I could and for me that was interesting because I wanted to
that was interesting because I wanted to
that was interesting because I wanted to do something that nobody else had done
do something that nobody else had done
do something that nobody else had done before so I did this at the University
before so I did this at the University
before so I did this at the University of Glasgow my PhD this is not to be
of Glasgow my PhD this is not to be
of Glasgow my PhD this is not to be confused with Hogwarts because it does
confused with Hogwarts because it does
confused with Hogwarts because it does look like Hogwarts interestingly my
look like Hogwarts interestingly my
look like Hogwarts interestingly my undergraduates and my student
undergraduates and my student
undergraduates and my student evaluations always say that I look like
evaluations always say that I look like
evaluations always say that I look like Harry Potter but I
Harry Potter but I
Harry Potter but I I really don’t think I do so I grew a
I really don’t think I do so I grew a
I really don’t think I do so I grew a beard to try and stop these comparisons
beard to try and stop these comparisons
beard to try and stop these comparisons and that didn’t work out too well moving
and that didn’t work out too well moving
and that didn’t work out too well moving on I went to Yale University for my
on I went to Yale University for my
on I went to Yale University for my postdoc and at Yale University I
postdoc and at Yale University I
postdoc and at Yale University I discovered a new field of research
discovered a new field of research
discovered a new field of research medicinal chemistry and the molecules
medicinal chemistry and the molecules
medicinal chemistry and the molecules that I made had a purpose and that
that I made had a purpose and that
that I made had a purpose and that purpose was to actually kill selectively
purpose was to actually kill selectively
purpose was to actually kill selectively cancer cells over healthy cells and for
cancer cells over healthy cells and for
cancer cells over healthy cells and for us and for me that was transformational
us and for me that was transformational
us and for me that was transformational I really wanted to do this as part of my
I really wanted to do this as part of my
I really wanted to do this as part of my future career it was hugely rewarding so
future career it was hugely rewarding so
future career it was hugely rewarding so today I’m going to tell you about what
today I’m going to tell you about what
today I’m going to tell you about what we did and what we did at Yale was
we did and what we did at Yale was
we did and what we did at Yale was target stat 3 and this is the first time
target stat 3 and this is the first time
target stat 3 and this is the first time that I was introduced to this protein
that I was introduced to this protein
that I was introduced to this protein and I found this protein really
and I found this protein really
and I found this protein really interesting because it was termed a
interesting because it was termed a
interesting because it was termed a master regulator of the cancer cell that
master regulator of the cancer cell that
master regulator of the cancer cell that drove the processes which made the
drove the processes which made the
drove the processes which made the cancer cell behave the way that it does
cancer cell behave the way that it does
cancer cell behave the way that it does to form tumors and for me this was
to form tumors and for me this was
to form tumors and for me this was something that I wanted to do so I’m
something that I wanted to do so I’m
something that I wanted to do so I’m going to tell you a little bit about
going to tell you a little bit about
going to tell you a little bit about stat 3 as you can probably tell I’m
stat 3 as you can probably tell I’m
stat 3 as you can probably tell I’m Scottish I’ve been here for 10 years but
Scottish I’ve been here for 10 years but
Scottish I’ve been here for 10 years but my accent hasn’t changed very much and
my accent hasn’t changed very much and
my accent hasn’t changed very much and I’m from a little island on the west
I’m from a little island on the west
I’m from a little island on the west coast of Scotland called Butte and if
coast of Scotland called Butte and if
coast of Scotland called Butte and if you look at the shape of Butte it looks
you look at the shape of Butte it looks
you look at the shape of Butte it looks almost identical to stat3 so
almost identical to stat3 so
almost identical to stat3 so so maybe me maybe it was fate that I was
so maybe me maybe it was fate that I was
so maybe me maybe it was fate that I was meant to target this protein so I’m
meant to target this protein so I’m
meant to target this protein so I’m going to tell your story about making
going to tell your story about making
going to tell your story about making drugs today legal ones not like breaking
drugs today legal ones not like breaking
drugs today legal ones not like breaking bad but what I can tell you is that if
bad but what I can tell you is that if
bad but what I can tell you is that if you’ve T students decided to make crack
you’ve T students decided to make crack
you’ve T students decided to make crack it could make it way better than
it could make it way better than
it could make it way better than Heisenberg but of course they wouldn’t
Heisenberg but of course they wouldn’t
Heisenberg but of course they wouldn’t do that now I’m going to tell you about
do that now I’m going to tell you about
do that now I’m going to tell you about stat 3 so stat 3 master regulator of
stat 3 so stat 3 master regulator of
stat 3 so stat 3 master regulator of cancer drives the cancer cell processes
cancer drives the cancer cell processes
cancer drives the cancer cell processes and what’s most interesting about
and what’s most interesting about
and what’s most interesting about there’s protein in the cancer cell is
there’s protein in the cancer cell is
there’s protein in the cancer cell is that if we knock it out we find that the
that if we knock it out we find that the
that if we knock it out we find that the cancer cell actually commits suicide so
cancer cell actually commits suicide so
cancer cell actually commits suicide so drugs targeting this protein can make
drugs targeting this protein can make
drugs targeting this protein can make the cancer cells commit suicide and die
the cancer cells commit suicide and die
the cancer cells commit suicide and die so this seems like a really appealing
so this seems like a really appealing
so this seems like a really appealing target so why do drugs work in the human
target so why do drugs work in the human
target so why do drugs work in the human body well to answer this you have to
body well to answer this you have to
body well to answer this you have to think of yourself at the highest – loans
think of yourself at the highest – loans
think of yourself at the highest – loans of educated society you have to think of
of educated society you have to think of
of educated society you have to think of yourself as a chemist an organic chemist
yourself as a chemist an organic chemist
yourself as a chemist an organic chemist an organic chemist see the human body in
an organic chemist see the human body in
an organic chemist see the human body in terms of a large reaction chamber we see
terms of a large reaction chamber we see
terms of a large reaction chamber we see it as a collection of large and small
it as a collection of large and small
it as a collection of large and small molecules that are undergoing chemical
molecules that are undergoing chemical
molecules that are undergoing chemical reactions complex ation events to
reactions complex ation events to
reactions complex ation events to mediate the processes the biological
mediate the processes the biological
mediate the processes the biological processes that allow us to function as
processes that allow us to function as
processes that allow us to function as human beings for example serotonin the
human beings for example serotonin the
human beings for example serotonin the small neurotransmitter found in the
small neurotransmitter found in the
small neurotransmitter found in the brain and then the GI tract binds to try
brain and then the GI tract binds to try
brain and then the GI tract binds to try and get to receptors to give some of our
and get to receptors to give some of our
and get to receptors to give some of our functions today are levels of anxiety or
functions today are levels of anxiety or
functions today are levels of anxiety or levels of depression depend on this
levels of depression depend on this
levels of depression depend on this interaction with receptors the key point
interaction with receptors the key point
interaction with receptors the key point is that drugs interact with molecules
is that drugs interact with molecules
is that drugs interact with molecules and we can do this positively or
and we can do this positively or
and we can do this positively or negatively
negatively
negatively to regulate biological processes until
to regulate biological processes until
to regulate biological processes until sa biological responses in a human so
sa biological responses in a human so
sa biological responses in a human so what is medicinal chemistry at its most
what is medicinal chemistry at its most
what is medicinal chemistry at its most fundamental level it’s the design and
fundamental level it’s the design and
fundamental level it’s the design and synthesis of molecules that bind to a
synthesis of molecules that bind to a
synthesis of molecules that bind to a target receptor typically a protein with
target receptor typically a protein with
target receptor typically a protein with exquisite selectivity and potency and
exquisite selectivity and potency and
exquisite selectivity and potency and the result of this complex is a
the result of this complex is a
the result of this complex is a biological response and in cancer
biological response and in cancer
biological response and in cancer research that biological response has to
research that biological response has to
research that biological response has to be death we want to see our drug binding
be death we want to see our drug binding
be death we want to see our drug binding to your target and leading to the cancer
to your target and leading to the cancer
to your target and leading to the cancer cell dying so why does it need to be
cell dying so why does it need to be
cell dying so why does it need to be potent it has to be potent because we
potent it has to be potent because we
potent it has to be potent because we want to use very little of it why does
want to use very little of it why does
want to use very little of it why does it need to be selective because our
it need to be selective because our
it need to be selective because our target isn’t the only protein that is in
target isn’t the only protein that is in
target isn’t the only protein that is in the cancer cell or the human body
the cancer cell or the human body
the cancer cell or the human body there’s lots of different targets so to
there’s lots of different targets so to
there’s lots of different targets so to give you a sense of the numbers and this
give you a sense of the numbers and this
give you a sense of the numbers and this is pretty our filling when you think
is pretty our filling when you think
is pretty our filling when you think about it the average drug dose gives the
about it the average drug dose gives the
about it the average drug dose gives the human body 10 to the 18 molecules so
human body 10 to the 18 molecules so
human body 10 to the 18 molecules so that’s a lot of zeros there is 10 to the
that’s a lot of zeros there is 10 to the
that’s a lot of zeros there is 10 to the 14 cells in the typical human being each
14 cells in the typical human being each
14 cells in the typical human being each cell contains 10 to the 10 molecules so
cell contains 10 to the 10 molecules so
cell contains 10 to the 10 molecules so if you do the math it’s a pretty amazing
if you do the math it’s a pretty amazing
if you do the math it’s a pretty amazing number that for your drug to find its
number that for your drug to find its
number that for your drug to find its target it is a one-in-a-million chance
target it is a one-in-a-million chance
target it is a one-in-a-million chance so it tells you that when you get into
so it tells you that when you get into
so it tells you that when you get into the cell you want to be binding to your
the cell you want to be binding to your
the cell you want to be binding to your protein for long enough such that you’re
protein for long enough such that you’re
protein for long enough such that you’re less at that biological response before
less at that biological response before
less at that biological response before it disappears so where do we target so
it disappears so where do we target so
it disappears so where do we target so our idea was the target stat 3 but the
our idea was the target stat 3 but the
our idea was the target stat 3 but the active form of stat 3 is actually a
active form of stat 3 is actually a
active form of stat 3 is actually a protein dimer and what we wanted to do
protein dimer and what we wanted to do
protein dimer and what we wanted to do was to make molecules that could come in
was to make molecules that could come in
was to make molecules that could come in and break open this dimer the dimer is
and break open this dimer the dimer is
and break open this dimer the dimer is the active form of this protein so how
the active form of this protein so how
the active form of this protein so how did we do this well we took inspiration
did we do this well we took inspiration
did we do this well we took inspiration from me
from me
from me and we use nature to guide us in our
and we use nature to guide us in our
and we use nature to guide us in our drug discovery process and what you can
drug discovery process and what you can
drug discovery process and what you can see here is in yellow you’ve got this
see here is in yellow you’ve got this
see here is in yellow you’ve got this protein complex and this is actually DNA
protein complex and this is actually DNA
protein complex and this is actually DNA bound in the middle you can see that
bound in the middle you can see that
bound in the middle you can see that this dimer is mediated by interaction
this dimer is mediated by interaction
this dimer is mediated by interaction with the yellow parts of the protein
with the yellow parts of the protein
with the yellow parts of the protein which are shown to bind to the protein
which are shown to bind to the protein
which are shown to bind to the protein and so our idea was can we take this
and so our idea was can we take this
and so our idea was can we take this small sequence and use it to inspire the
small sequence and use it to inspire the
small sequence and use it to inspire the design of small molecules which will
design of small molecules which will
design of small molecules which will bind with higher potency and selectivity
bind with higher potency and selectivity
bind with higher potency and selectivity than stat3 itself and disrupt this
than stat3 itself and disrupt this
than stat3 itself and disrupt this active form so medicinal chemistry is a
active form so medicinal chemistry is a
active form so medicinal chemistry is a little bit like a jigsaw puzzle we’re
little bit like a jigsaw puzzle we’re
little bit like a jigsaw puzzle we’re trying to fit the molecular pieces into
trying to fit the molecular pieces into
trying to fit the molecular pieces into the active site so that it binds
the active site so that it binds
the active site so that it binds potently and selectively these are two
potently and selectively these are two
potently and selectively these are two words that I’m going to be using a lot
words that I’m going to be using a lot
words that I’m going to be using a lot in this talk so if we look at the active
in this talk so if we look at the active
in this talk so if we look at the active site there’s three main pockets within
site there’s three main pockets within
site there’s three main pockets within this protein so we want to make
this protein so we want to make
this protein so we want to make molecules that bind to all three of
molecules that bind to all three of
molecules that bind to all three of those pockets so this is a molecule that
those pockets so this is a molecule that
those pockets so this is a molecule that came up through a computational screen
came up through a computational screen
came up through a computational screen we’re going to call it compound one and
we’re going to call it compound one and
we’re going to call it compound one and it’s got a nice e-50 of 90 micro molar
it’s got a nice e-50 of 90 micro molar
it’s got a nice e-50 of 90 micro molar so what’s an at and I see 50 and I see
so what’s an at and I see 50 and I see
so what’s an at and I see 50 and I see 50 is the concentration of drug that’s
50 is the concentration of drug that’s
50 is the concentration of drug that’s required to kill 50 percent of the cells
required to kill 50 percent of the cells
required to kill 50 percent of the cells so micromolar suggests it’s very small
so micromolar suggests it’s very small
so micromolar suggests it’s very small if you remember your organic chemistry
if you remember your organic chemistry
if you remember your organic chemistry you’ll know that this is a very small
you’ll know that this is a very small
you’ll know that this is a very small amount of material but in fact that’s
amount of material but in fact that’s
amount of material but in fact that’s quite a lot when we consider what it
quite a lot when we consider what it
quite a lot when we consider what it takes to be a drug to be a drug you need
takes to be a drug to be a drug you need
takes to be a drug to be a drug you need to have a number closer to 0.5 200 times
to have a number closer to 0.5 200 times
to have a number closer to 0.5 200 times more potent so you need two hundred
more potent so you need two hundred
more potent so you need two hundred times less drug to kill the same amount
times less drug to kill the same amount
times less drug to kill the same amount of cancer cells so what did we do well
of cancer cells so what did we do well
of cancer cells so what did we do well we decided that to do this properly we
we decided that to do this properly we
we decided that to do this properly we needed to find a piece that could fit in
needed to find a piece that could fit in
needed to find a piece that could fit in that top pocket so that we’re tailoring
that top pocket so that we’re tailoring
that top pocket so that we’re tailoring the molecule for that particular protein
the molecule for that particular protein
the molecule for that particular protein so we built the molecule we added to our
so we built the molecule we added to our
so we built the molecule we added to our structure so that we’re fitting in to
structure so that we’re fitting in to
structure so that we’re fitting in to this top part of the pocket and you can
this top part of the pocket and you can
this top part of the pocket and you can see that
see that
see that kinda like a jigsaw puzzle so what do we
kinda like a jigsaw puzzle so what do we
kinda like a jigsaw puzzle so what do we do what is the process for making
do what is the process for making
do what is the process for making molecules that kill cancer cells how do
molecules that kill cancer cells how do
molecules that kill cancer cells how do we rank them and assess them well first
we rank them and assess them well first
we rank them and assess them well first of all we have to make them and we make
of all we have to make them and we make
of all we have to make them and we make them with organic chemistry which is
them with organic chemistry which is
them with organic chemistry which is everyone’s favorite subject at
everyone’s favorite subject at
everyone’s favorite subject at university I know my students love me
university I know my students love me
university I know my students love me and they love being taught organic
and they love being taught organic
and they love being taught organic chemistry
biologists call as cooks they call as
biologists call as cooks they call as coops because we mix things together and
coops because we mix things together and
coops because we mix things together and something comes out at the end they
something comes out at the end they
something comes out at the end they obviously have an inferiority complex
obviously have an inferiority complex
obviously have an inferiority complex and this inferiority complex stems from
and this inferiority complex stems from
and this inferiority complex stems from the fact that chemists are able to
the fact that chemists are able to
the fact that chemists are able to manipulate material at the atomic level
manipulate material at the atomic level
manipulate material at the atomic level we can do so many things with molecules
we can do so many things with molecules
we can do so many things with molecules we can even time travel as then we can
we can even time travel as then we can
we can even time travel as then we can make old mand excited we were looking
make old mand excited we were looking
make old mand excited we were looking out for ourselves so so the first step
out for ourselves so so the first step
out for ourselves so so the first step is to make molecules so here’s a typical
is to make molecules so here’s a typical
is to make molecules so here’s a typical synthetic scheme we don’t just make one
synthetic scheme we don’t just make one
synthetic scheme we don’t just make one molecule we make on average maybe 25 to
molecule we make on average maybe 25 to
molecule we make on average maybe 25 to 50 molecules in the first pass and we’re
50 molecules in the first pass and we’re
50 molecules in the first pass and we’re just going to denis denote them as
just going to denis denote them as
just going to denis denote them as little shapes here so what’s the next
little shapes here so what’s the next
little shapes here so what’s the next step the next step is to test whether it
step the next step is to test whether it
step the next step is to test whether it binds to the protein so we do this
binds to the protein so we do this
binds to the protein so we do this outside of the cell because if it
outside of the cell because if it
outside of the cell because if it doesn’t bind outside of the cell it’s
doesn’t bind outside of the cell it’s
doesn’t bind outside of the cell it’s not going to bind inside the cell so the
not going to bind inside the cell so the
not going to bind inside the cell so the idea is that we’re looking for a
idea is that we’re looking for a
idea is that we’re looking for a molecule that sticks with high affinity
molecule that sticks with high affinity
molecule that sticks with high affinity to this protein what’s the next stage
to this protein what’s the next stage
to this protein what’s the next stage the next stage is to see whether it is
the next stage is to see whether it is
the next stage is to see whether it is selective and we do this by screening
selective and we do this by screening
selective and we do this by screening against different proteins that are both
against different proteins that are both
against different proteins that are both similar and different and what we want
similar and different and what we want
similar and different and what we want to see is that the molecule does not
to see is that the molecule does not
to see is that the molecule does not bind to the protein it’s not a
bind to the protein it’s not a
bind to the protein it’s not a promiscuous drug
promiscuous drug
promiscuous drug so so then the next step is we put it
so so then the next step is we put it
so so then the next step is we put it into cells so we put it into cancer
into cells so we put it into cancer
into cells so we put it into cancer cells we dose the cancer cells and what
cells we dose the cancer cells and what
cells we dose the cancer cells and what we’re looking for we’re looking to see
we’re looking for we’re looking to see
we’re looking for we’re looking to see that the drug does what it’s supposed to
that the drug does what it’s supposed to
that the drug does what it’s supposed to do which is to actually kill the cells
do which is to actually kill the cells
do which is to actually kill the cells if it kills the cells the molecule moves
if it kills the cells the molecule moves
if it kills the cells the molecule moves forward what’s the next stage
forward what’s the next stage
forward what’s the next stage selectivity does it kill normal cells do
selectivity does it kill normal cells do
selectivity does it kill normal cells do we see a selectivity of effect for
we see a selectivity of effect for
we see a selectivity of effect for cancer relative to healthy cells and
cancer relative to healthy cells and
cancer relative to healthy cells and ultimately we want to see as no effect
ultimately we want to see as no effect
ultimately we want to see as no effect whatsoever so the next stage is we have
whatsoever so the next stage is we have
whatsoever so the next stage is we have to do some cell biology we have to look
to do some cell biology we have to look
to do some cell biology we have to look inside the cell and see whether we’re
inside the cell and see whether we’re
inside the cell and see whether we’re knocking out a protein target so what we
knocking out a protein target so what we
knocking out a protein target so what we want to see is with increasing
want to see is with increasing
want to see is with increasing concentrations of drug that we see a
concentrations of drug that we see a
concentrations of drug that we see a decreasing amount of our protein and you
decreasing amount of our protein and you
decreasing amount of our protein and you can see it here then what do we do we
can see it here then what do we do we
can see it here then what do we do we look at other targets inside the cancer
look at other targets inside the cancer
look at other targets inside the cancer cell we want to see is it hitting
cell we want to see is it hitting
cell we want to see is it hitting everything and the goal will be to see
everything and the goal will be to see
everything and the goal will be to see that actually nothing happens to other
that actually nothing happens to other
that actually nothing happens to other cells unless they’re related to our
cells unless they’re related to our
cells unless they’re related to our protein we want to see no effect we want
protein we want to see no effect we want
protein we want to see no effect we want to see an effect on our target so the
to see an effect on our target so the
to see an effect on our target so the final stages looking in vivo so in
final stages looking in vivo so in
final stages looking in vivo so in cancer research we engraft mice with
cancer research we engraft mice with
cancer research we engraft mice with human tumors and we dose the mice with
human tumors and we dose the mice with
human tumors and we dose the mice with our drug with two objectives the first
our drug with two objectives the first
our drug with two objectives the first objective is to see whether or not the
objective is to see whether or not the
objective is to see whether or not the drug is efficacious does it shrink the
drug is efficacious does it shrink the
drug is efficacious does it shrink the tumor in the mouse and the other thing
tumor in the mouse and the other thing
tumor in the mouse and the other thing is is it toxic we’re going into a living
is is it toxic we’re going into a living
is is it toxic we’re going into a living system we want to see whether or not we
system we want to see whether or not we
system we want to see whether or not we have serious side effects as a result of
have serious side effects as a result of
have serious side effects as a result of this drug so what did we do so we
this drug so what did we do so we
this drug so what did we do so we started off with this molecule compound
started off with this molecule compound
started off with this molecule compound 1 it’s got an IC 50 of 90 and remember
1 it’s got an IC 50 of 90 and remember
1 it’s got an IC 50 of 90 and remember what we’re trying to do is to make that
what we’re trying to do is to make that
what we’re trying to do is to make that number significantly smaller we want to
number significantly smaller we want to
number significantly smaller we want to see this number dropping way down so
see this number dropping way down so
see this number dropping way down so you’ve T we have a strict
you’ve T we have a strict
you’ve T we have a strict your process so people like me have to
your process so people like me have to
your process so people like me have to do well not just in one project but in
do well not just in one project but in
do well not just in one project but in multiple projects or else we get fired
multiple projects or else we get fired
multiple projects or else we get fired so bearing that in mind we made our
so bearing that in mind we made our
so bearing that in mind we made our first change and our first change was to
first change and our first change was to
first change and our first change was to get rid of this oxygen replace it with a
get rid of this oxygen replace it with a
get rid of this oxygen replace it with a nitrogen and that turned out horribly so
nitrogen and that turned out horribly so
nitrogen and that turned out horribly so at this point I was thinking of career
at this point I was thinking of career
at this point I was thinking of career choices in Scotland cuz Canada was gonna
choices in Scotland cuz Canada was gonna
choices in Scotland cuz Canada was gonna kick me out and so but remember the
kick me out and so but remember the
kick me out and so but remember the policy that we had that we wanted to
policy that we had that we wanted to
policy that we had that we wanted to access this upper pocket of the stat
access this upper pocket of the stat
access this upper pocket of the stat protein so we put in a benzyl group 300
protein so we put in a benzyl group 300
protein so we put in a benzyl group 300 para cyano 260 Terra butyl 190 by phenol
para cyano 260 Terra butyl 190 by phenol
para cyano 260 Terra butyl 190 by phenol 115 cyclohexyl benzyl for micro molar so
115 cyclohexyl benzyl for micro molar so
115 cyclohexyl benzyl for micro molar so this compound is now twenty times more
this compound is now twenty times more
this compound is now twenty times more active than the first molecule so that
active than the first molecule so that
active than the first molecule so that was really exciting we were very happy
was really exciting we were very happy
was really exciting we were very happy but it wasn’t good enough we wanted to
but it wasn’t good enough we wanted to
but it wasn’t good enough we wanted to be into the 0.5 region in terms of going
be into the 0.5 region in terms of going
be into the 0.5 region in terms of going forward into animals so we meet some
forward into animals so we meet some
forward into animals so we meet some more changes and I’ll summarize it very
more changes and I’ll summarize it very
more changes and I’ll summarize it very briefly by saying that we discovered
briefly by saying that we discovered
briefly by saying that we discovered this molecule bp1 102 so we changed this
this molecule bp1 102 so we changed this
this molecule bp1 102 so we changed this part of the inhibitor and so this
part of the inhibitor and so this
part of the inhibitor and so this molecule was way more potent it was 0.8
molecule was way more potent it was 0.8
molecule was way more potent it was 0.8 micro molar so we were getting more and
micro molar so we were getting more and
micro molar so we were getting more and more potent we’re using less drug to
more potent we’re using less drug to
more potent we’re using less drug to kill the same number of cancer cells so
kill the same number of cancer cells so
kill the same number of cancer cells so what did it doing cells so in healthy
what did it doing cells so in healthy
what did it doing cells so in healthy cells we found that had no stat3
cells we found that had no stat3
cells we found that had no stat3 we saw the no effect really on the metal
we saw the no effect really on the metal
we saw the no effect really on the metal when we put them into cells that had
when we put them into cells that had
when we put them into cells that had stat3 and more tumour cells we saw that
stat3 and more tumour cells we saw that
stat3 and more tumour cells we saw that it killed the cells really really nicely
it killed the cells really really nicely
it killed the cells really really nicely and so then we decided to move into cell
and so then we decided to move into cell
and so then we decided to move into cell biology and we saw with increasing
biology and we saw with increasing
biology and we saw with increasing concentrations of drug that our molecule
concentrations of drug that our molecule
concentrations of drug that our molecule decreased the amount of stat3
decreased the amount of stat3
decreased the amount of stat3 so it showed us that we’re on target we
so it showed us that we’re on target we
so it showed us that we’re on target we were selective for cancer cells over a
were selective for cancer cells over a
were selective for cancer cells over a healthy cells so now what did it do in
healthy cells so now what did it do in
healthy cells so now what did it do in an animal
an animal
an animal so the first thing we do is we test in a
so the first thing we do is we test in a
so the first thing we do is we test in a mouse so we inject it into the mouse and
mouse so we inject it into the mouse and
mouse so we inject it into the mouse and we look to see how much drug is there
we look to see how much drug is there
we look to see how much drug is there and for how long so the interesting
and for how long so the interesting
and for how long so the interesting thing about animals and humans is that
thing about animals and humans is that
thing about animals and humans is that they have a lever and a lever is
they have a lever and a lever is
they have a lever and a lever is responsible for thrashing most drug
responsible for thrashing most drug
responsible for thrashing most drug discovery dreams because they deliver is
discovery dreams because they deliver is
discovery dreams because they deliver is full of enzymes that metabolize drugs so
full of enzymes that metabolize drugs so
full of enzymes that metabolize drugs so think of the analogy of the jigsaw
think of the analogy of the jigsaw
think of the analogy of the jigsaw puzzle and think about all the time that
puzzle and think about all the time that
puzzle and think about all the time that my pure graduate students put in to
my pure graduate students put in to
my pure graduate students put in to identifying this molecule and then they
identifying this molecule and then they
identifying this molecule and then they inject it into mice and guess what
inject it into mice and guess what
inject it into mice and guess what happens it completely changes the entire
happens it completely changes the entire
happens it completely changes the entire structure is different and that sucks
structure is different and that sucks
structure is different and that sucks because it doesn’t fit in the protein
because it doesn’t fit in the protein
because it doesn’t fit in the protein anymore and we have to go back to the
anymore and we have to go back to the
anymore and we have to go back to the drawing board to give you an idea of how
drawing board to give you an idea of how
drawing board to give you an idea of how efficient their lever is this drug is
efficient their lever is this drug is
efficient their lever is this drug is gone within 10 minutes in the animal
gone within 10 minutes in the animal
gone within 10 minutes in the animal completely gone there’s nothing left so
completely gone there’s nothing left so
completely gone there’s nothing left so what do we do like so many things we
what do we do like so many things we
what do we do like so many things we rely on chemistry and we rely on
rely on chemistry and we rely on
rely on chemistry and we rely on chemistry to stabilize these parts of
chemistry to stabilize these parts of
chemistry to stabilize these parts of the molecule there are considered weak
the molecule there are considered weak
the molecule there are considered weak to metabolic enzymes so to cut a long
to metabolic enzymes so to cut a long
to metabolic enzymes so to cut a long story short we ended up making this
story short we ended up making this
story short we ended up making this molecule which is a derivative of BP 1 1
molecule which is a derivative of BP 1 1
molecule which is a derivative of BP 1 1 or 2 and we saw that this molecule was
or 2 and we saw that this molecule was
or 2 and we saw that this molecule was way more stable in fact it has a
way more stable in fact it has a
way more stable in fact it has a half-life of over 4 hours so this was
half-life of over 4 hours so this was
half-life of over 4 hours so this was really exciting and then we did some
really exciting and then we did some
really exciting and then we did some more chemistry but it’s patent-protected
more chemistry but it’s patent-protected
more chemistry but it’s patent-protected so we can show you the structure but
so we can show you the structure but
so we can show you the structure but we’ll call it compound X 4 for my
we’ll call it compound X 4 for my
we’ll call it compound X 4 for my venture capitalists
venture capitalists
venture capitalists so we went into a multiple myeloma trial
so we went into a multiple myeloma trial
so we went into a multiple myeloma trial so multiple myeloma is a hundred percent
so multiple myeloma is a hundred percent
so multiple myeloma is a hundred percent lethal disease it’s a really toxic
lethal disease it’s a really toxic
lethal disease it’s a really toxic cancer that claims everyone who
cancer that claims everyone who
cancer that claims everyone who eventually who gets it so right now
eventually who gets it so right now
eventually who gets it so right now there is no cure for it so I’m going to
there is no cure for it so I’m going to
there is no cure for it so I’m going to show you the effect of our drug in
show you the effect of our drug in
show you the effect of our drug in multiple myeloma and I’ve shown you a
multiple myeloma and I’ve shown you a
multiple myeloma and I’ve shown you a series of images here which are really
series of images here which are really
series of images here which are really cool and I’ll just state that again that
cool and I’ll just state that again that
cool and I’ll just state that again that these are really cool images because
these are really cool images because
these are really cool images because your idea of cool and mine might be
your idea of cool and mine might be
your idea of cool and mine might be quite different so what you’re seeing
quite different so what you’re seeing
quite different so what you’re seeing here in these mice is actually a tumor
here in these mice is actually a tumor
here in these mice is actually a tumor but you’re also seeing stat 3 so stat 3
but you’re also seeing stat 3 so stat 3
but you’re also seeing stat 3 so stat 3 activity the is labeled so you see this
activity the is labeled so you see this
activity the is labeled so you see this fluorescent dye is associated with stat
fluorescent dye is associated with stat
fluorescent dye is associated with stat function so what we did was we treated
function so what we did was we treated
function so what we did was we treated with compound X and what we showed in a
with compound X and what we showed in a
with compound X and what we showed in a time-dependent manner over a two-hour
time-dependent manner over a two-hour
time-dependent manner over a two-hour period was the air molecule shut down
period was the air molecule shut down
period was the air molecule shut down stat 3 inside a human tumor inside a
stat 3 inside a human tumor inside a
stat 3 inside a human tumor inside a mouse model which we thought was really
mouse model which we thought was really
mouse model which we thought was really cool we then went into a major law
cool we then went into a major law
cool we then went into a major law blastoma trial
blastoma trial
blastoma trial medulloblastoma being one of the most
medulloblastoma being one of the most
medulloblastoma being one of the most common brain cancers in children 70% of
common brain cancers in children 70% of
common brain cancers in children 70% of the patients are treated with really a
the patients are treated with really a
the patients are treated with really a horrible cocktail of drugs and radiation
horrible cocktail of drugs and radiation
horrible cocktail of drugs and radiation survive they’re left with severe side
survive they’re left with severe side
survive they’re left with severe side effects that they’ll take with them
effects that they’ll take with them
effects that they’ll take with them their entire life the other 30 to 35%
their entire life the other 30 to 35%
their entire life the other 30 to 35% are palliative
are palliative
are palliative there is no cure option for them the
there is no cure option for them the
there is no cure option for them the tumor spreads down the spinal column so
tumor spreads down the spinal column so
tumor spreads down the spinal column so we wanted to see whether our stat 3 drug
we wanted to see whether our stat 3 drug
we wanted to see whether our stat 3 drug would have an effect on this recurrent
would have an effect on this recurrent
would have an effect on this recurrent medulloblastoma the medulloblastoma that
medulloblastoma the medulloblastoma that
medulloblastoma the medulloblastoma that is completely untreatable right now and
is completely untreatable right now and
is completely untreatable right now and what I’ll show you is two things here is
what I’ll show you is two things here is
what I’ll show you is two things here is brains slices taken from mice they’ve
brains slices taken from mice they’ve
brains slices taken from mice they’ve got these brain tumors and you can see
got these brain tumors and you can see
got these brain tumors and you can see the tumors in purple and then we treat
the tumors in purple and then we treat
the tumors in purple and then we treat with compound X and what we saw was
with compound X and what we saw was
with compound X and what we saw was really stunning regression of an
really stunning regression of an
really stunning regression of an untreatable tumor so this clearly got as
untreatable tumor so this clearly got as
untreatable tumor so this clearly got as very
very
very excited and just to show you that it
excited and just to show you that it
excited and just to show you that it actually has a deference on the quality
actually has a deference on the quality
actually has a deference on the quality of life of these mice that have human
of life of these mice that have human
of life of these mice that have human tumors this is a we’ve video and what
tumors this is a we’ve video and what
tumors this is a we’ve video and what you can see here is a mouse that has
you can see here is a mouse that has
you can see here is a mouse that has been treated with compound X and a mouse
been treated with compound X and a mouse
been treated with compound X and a mouse that has no drug and it just shows you
that has no drug and it just shows you
that has no drug and it just shows you the most that is treated with our drug
the most that is treated with our drug
the most that is treated with our drug is quite happy and behaving like a mouse
is quite happy and behaving like a mouse
is quite happy and behaving like a mouse does energetic and inquisitive whereas
does energetic and inquisitive whereas
does energetic and inquisitive whereas the most that is that no drug is clearly
the most that is that no drug is clearly
the most that is that no drug is clearly more abundant so finally to summarize I
more abundant so finally to summarize I
more abundant so finally to summarize I hope I’ve shown you in the course of
hope I’ve shown you in the course of
hope I’ve shown you in the course of this talk the rational approach that
this talk the rational approach that
this talk the rational approach that made chemists take to discover new
made chemists take to discover new
made chemists take to discover new molecules and we’ve gone from a really
molecules and we’ve gone from a really
molecules and we’ve gone from a really horrible compound to what we think is a
horrible compound to what we think is a
horrible compound to what we think is a really good compound for treating
really good compound for treating
really good compound for treating untreatable orphan diseases right now
untreatable orphan diseases right now
untreatable orphan diseases right now compound X this compound has just
compound X this compound has just
compound X this compound has just received Series A funding so we’re
received Series A funding so we’re
received Series A funding so we’re hopeful that we’ll be in clinical trials
hopeful that we’ll be in clinical trials
hopeful that we’ll be in clinical trials now within the next 24 months and I will
now within the next 24 months and I will
now within the next 24 months and I will add the caveat that it is borrowing hair
add the caveat that it is borrowing hair
add the caveat that it is borrowing hair cups medicinal chemistry and drug
cups medicinal chemistry and drug
cups medicinal chemistry and drug discovery throws up hair cups all the
discovery throws up hair cups all the
discovery throws up hair cups all the time and hopefully we don’t experience
time and hopefully we don’t experience
time and hopefully we don’t experience any more and finally I’d just like to
any more and finally I’d just like to
any more and finally I’d just like to acknowledge my research group these guys
acknowledge my research group these guys
acknowledge my research group these guys do all the work they’re the ones that
do all the work they’re the ones that
do all the work they’re the ones that are making the molecules testing them
are making the molecules testing them
are making the molecules testing them and I just have the pleasure of telling
and I just have the pleasure of telling
and I just have the pleasure of telling you about it and thank you for your
you about it and thank you for your
you about it and thank you for your attention
attention
attention [Music]
[Music]
[Music] [Applause]
”
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