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Our first speaker is Iolanda Micco.
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She's the Head of Discovery and Chemistry in Axiom.
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Yolanda is Head of Discovery and Chemistry at Axxam with over 15 years of international experience in drug discovery.
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She holds a PhD in medicinal chemistry from 2 from the University of Siena.
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Previously, she directed medicinal chemistry at Scandium Oncology, served as Associate Director at Viper Gen, taught in Singapore, and LED drug discovery at Vienna Biotech.
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So today I'm going to talk about undruggable targets and what we can do in that regard, let's start from this picture here.
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What do we do when we are in front of an apple tree and we want to start picking apples?
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We probably start picking apples from the bottom of the tree.
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So after a while that we are picking apples.
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That's the situation we are facing.
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We have all the apples taken from the bottom of the tree and we have all remaining apples on the top of the tree.
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Those are challenging to be picked up.
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So we need to be either creative or we need to have a tool.
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So why am I talking about an apple tree on a drug discovery conference?
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Well, this is a metaphor.
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On the left hand side, the apple tree represents the biotech industry from the 90s and on the right hand side, the apple tree represents the biotech industry today.
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So we have been picking up a lot of things during the years, which is good.
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We have managed and handled a lot of easier targets.
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So now we have those more undruggable.
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That's what it is.
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We were not lazy, we're just as smart.
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You need to start from what is easier to do.
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So as always, you know, I think now I need to get out of the metaphor.
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So let's talk about science.
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What is undruggable target?
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So I think if we want to make like if you want to give a definition in one sentence, we have an undruggable targets every time we have no clue how to access that target.
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That can be for many different reasons.
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It can be because the cavity is not reachable or maybe the binding pocket is really shallow, very floppy, or maybe I have no clue about the protein structure.
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I don't know anything about ligands, or I don't know anything about how to assay that protein.
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So that can be many reasons.
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But overall, the ultimate consequence is that target is an undruggable one.
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Now, every time in science we are challenging ourselves in trying to go in a different direction. There are always two groups of people to groups of scientists.
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There are conservative scientists and more sort of how to say innovative scientist.
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But there is one thing that usually makes things change.
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This is usually pretty much stable kind of ratio between conservative and innovative.
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But then at some point you have a successful story that will change this balance, that will change this ratio, and eventually you have some game changers in the field.
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Now look at this.
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This is the proteome, the human proteome that in the last year has changed a lot because we have had an evolution in the field.
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So we might, we know, we also know much more than that we knew before.
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As you can see here, we knew a lot of things about druggable targets, but still the 80% of the human protein today looks intractable.
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That's the reality that we have to face that in some way we need to do something to go in that direction.
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So what I was saying earlier about conservative and innovative trends that you need to have some sort of game changers in the field, some successful story to convince the more conservative people that's the way to go.
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Well, we also had some game changers in the field of undruggable targets.
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We had some successful stories for pharmacological chaperones for just to mention an example with Tafamidis.
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She was approved recently for FoldRx which is a subsidiary of Pfizer.
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Lumacaftor, we have some protein degraders.
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It was an exploding field, the degraders one.
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But then we got some successful stories and many people got convinced it was maybe we could go in that direction.
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We had some covalent inhibition.
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That is the not a new concept we'll see later.
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But eventually at some point we got the first KRAS inhibitor coming from the covalent approach that was really convincing, and many people start to work on covalent inhibition again. Or again with Risdiplam, as a splicing modulator.
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That was one of the successful stories in that direction as well.
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So what happens in this case is that, for example, with the Lenalidomide, you have a successful story, and then all of a sudden there is a lesson learned, and the scientific community starts to be attracted, and investors has to be attracted.
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And that's how we can also read the sort of impact on the scientific publications.
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You can see here I got this plot from Drug Discovery Today 2023 in the then they represent there is nothing to do with the FDA approved of drugs.
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So this is just a PubMed like search count which is reflecting the interest in the scientific community.
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And you can see that in the last 10 years actually we got an impressive increase in interest on covalent inhibitors, degraders, PROTAC, molecular glues, RNA binders. Doesn't mean that the old or standard approach is not working.
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It will always still there, it will always still be there.
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But you can clearly see an increase of interest.
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That's what is happening.
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So we need to tackle this problem and in the main players in the field are biology and chemistry.
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We often, sometimes we fight together, we try to sort of find solution together.
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We fight, we don't agree, we don't understand each other's language, whatever.
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But in at the end, eventually we get surprised that we can actually find interesting and surprising solutions together.
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So that's the philosophy behind also Axxam’s approach.
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We always put biology and chemistry in the field.
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So we are trying to tackle the problem of undruggable targets in these two fields that eventually they converge together. In the field of biology, years ago, that's where we were: phenotypical assay, pathway assays were super cool, everything was working, but it was not enough at some point.
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So we started to kind of broader our prospects in the field where we wanted to put our hands.
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And eventually we started to increase our capabilities, expertise, facilities and so on with assays that allowed the measurement of transcriptional activity, assays that could allow the measurement of splicing, RNA splicing activities, assays that could measure the activity of protein degraders or imaging based assays like organellar function, or autophagy, and so on.
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So that's how we are trying to expand in the biology perspective.
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Bear with me, I'm not going to talk about biology too much today.
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Medchem sort of background.
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So I'm going to show you what we do in chemistry.
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That's where the next slides will be focused on.
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But we do more or less the same or the same kind of thinking. In chemistry, we have our universal libraries.
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That's where we start.
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It's good to have universal library.
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Yes.
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Will they die?
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No, never.
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I mean you will always have a universal collection that you will find useful, and you will need to bring forward.
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However, now we feel we need to kind of fuel the chemical space with something a little bit more specific.
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And that's how we started to have reached our chemical space in house with natural compounds, with PROTACs and molecular glues, with RNA splicing modulator, covalent binders, PPI modulators, macrocycles.
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I mean it's sometimes you might end up in a speculative sort of area.
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That's fine as well, but you need to give it a try if you want to tackle the problem.
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There's really literally no time to talk about everything in here.
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So we'll try to give you a glimpse of what we do in some of those specific and focused libraries.
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And then I'm happy also to talk later our booth, if you will.
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OK, so let's go on nature solutions for undruggable targets.
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I guess everybody agrees the nature is the mother of chemical interactions.
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Everything comes from there.
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OK, so on the left hand side we have the first natural compound from plants, which is the morphine.
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And on the right hand side we have the first natural compound from bacterial.
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And I mean those are really old compounds, but you can appreciate that the chemistry is quite complex, and you don't always have the luxury to go in an easy chemical expansion on those molecules.
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So whoever is there, it might help undruggable targets.
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And say why not?
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So we have at Axxam, we have natural collection with advanced extracts prefect and NatPure collection which is a plated collection of known natural compounds.
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This is the worldwide largest collection of natural compounds and is really highly diverse.
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It also has lot of variability and diversity in terms of the chemical matter that is in there.
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PPI, that's also something that we have to do right.
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And you can tackle the problem with antibody, with peptides, with small molecules, everything has pros and cons.
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For example, antibodies, they're cool, they're super specific, but they can access only extracellular targets.
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Whereas the small molecules, for example, the smaller they can go in the cell, but eventually they might be less specific or sometimes they go beyond the rule of five.
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So that's how we started to use machine learning approach to design and synthesise the library of protein-protein interactions inhibitors.
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And we use the transfer learning, reinforcement learning, using also machine learning classifiers to just sort of identify or design 120,000 molecules that have been then filtered through different parameters that you end up with the first subset of 3000 compounds.
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This is an exercise, we'll see how it goes.
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And but that's the direction we are taking into this.
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And now they are under synthesis.
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Covalent binders, it's an old story.
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I mean, the first covalent binder is aspirin.
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We're talking about the late 1800.
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So it's a, it's an old concept, but eventually at some point people didn't believe in it anymore because you have problems with toxicity, side reaction are difficult to reverse.
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And so it's it was a concern for people.
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But again, KRAS inhibitor was successful, and people started to work on them again.
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So we are designing or actually sorry, not designing, but we are preparing a library of covalent binders where you have to make sure that you have the right amount of warheads and right amount of diversity because you also want to be specific in the interaction with a binding pocket.
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So we've filtered through commercial covalent binders, and we selected 9000 compounds to get a collection with a pretty good distribution of warheads trying to target cystine, serine, and histidine, but also with a 36% of an unknown specificity.
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So eventually we can also target something else that you know like randomly you the determine as important.
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Last thing about the greater platform, this is an exercise we are doing with Symeres, who is also present today, the protein degraders, it's also an important field.
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We at Axxam have the abilities and the expertise to run a screening on degraders.
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Whereas Symeres has developed a platform to prepare pretty quickly a library of PROTACs starting from their E3 ligases and then and from their linkers in house.
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So they can, if you look at the numbers, they can quickly prepare between 100 and 600 PROTACs in house and have them screened in Axxam.
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Just the last comment, yes, new challenges, new rules.
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Every time you have a new challenge, you also need to embrace new rules.
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So we are witnessing actually an interesting trend here from the chemical perspective, as you can see from this slide here, those are either approved to drugs or in a very advanced stage like phase one or phase two.
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I mean, look at this structure here.
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This is a massive drug.
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It's not a small molecule.
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Some time ago, if I had proposed this to my boss, they’d have said no, but it's over there.
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It's actually orally bioavailable.
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And it's interesting.
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And those are just a few cases.
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And so my point here is that we are definitely witnessing a rise of compounds surpassing the rule of five.
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And you know, this kind of it's another lesson learned. Sometimes we definitely need to sort of embrace the bravery that we need to break the rules and change direction.
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So in conclusion, we are undergoing a sort of a transformation in the field.
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We need to bring all the capabilities, biology, chemistry on the pitch.
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We also need to be brave enough to break the rules sometimes and that's the only way to tackle the problem.
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So I think with that, I'd like to thank all the all of people in Axxam that contribute daily with passion and commitment.
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I would like to thank the organisers for having us here.
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I would like to thank all of you for your attention and I'm happy to take any question you might have.
