Transcript:
Hello, and welcome to Certara Talks. I’m Doctor Suzanne Minton, and I’m a director of content strategy at Certara . Today, I’m talking to my colleague, doctor Joshua Apgar. Joshua, welcome to Certara talks. Would you like to introduce yourself?
Sure. Thank you. I’m, Josh Apgar, one of the co founders at applied Balmain, recently joined the Certara team. And I’m really excited to be here. So thank you.
Awesome. Glad great to talk to you, and and so glad to have you and the ABM crew as part of the bigger Certara family.
So Josh, I hear that you recently got back from the molecular glue drug development summit meeting. Sounds very exciting. Can we, thought we could talk about it a bit? First of all, a lot of our audience probably isn’t familiar with what a molecular glue refers to. Can you talk about that, please?
Sure. So molecular glues are part of a larger family of a new pharmacology of drugs.
That looks to target intracellular proteins through to the proteolytic machinery as a way of degrading intracellular targets. And kind of the tagline has been drugging the undruggable.
For them. Molecular glues as a subtype of that are a type of molecule that really enhance existing protein protein interactions.
Within the cell, and kind of the prototypical example of that is thalidomide, which for a long time the mechanism of action was not known, and was later discovered to be one of these types of glues. And really what they do is by fitting into that protein protein interface that kind of helps stabilize that interaction and enhance the sort of the natural degradation machinery. And so these have found all kinds of life in, initially in cancer, but increasingly in immunological diseases. You know, in other places where being able to selectively target a protein, that’s not necessarily a kinase or one of the types of drugs that are easily Drugged, really enables sort of a whole new class of pharmacology to be opened up.
Very cool. It’s it’s a exciting emerging technology as as we were talking about earlier. When I was in grad school, I remember learning about, e three ligases, and that basic biology was was just, starting twenty years ago, and and now these molecules are starting to make it into the clinic. Can you talk about what you think are the challenges for molecular glues to get into the clinic and run through the drug development process to become approved therapies for patients.
Yeah. But as you can imagine, these molecules that have to fit in at these very compact, you know, protein protein interfaces. The chemistry has been really a big challenge there in getting enough interaction without disrupting the existing interaction has been really a challenge. And if you went to the con conference last year, a lot of the focus would have been on that. But as things are starting to move towards the clinic, you know, the other real promise here is that these could be orally bioavailable drugs that they could be given, you know, you know, in a, you know, regimen that’s very different than the bio therapeutics, which are all bio all injectables.
And so that means they have to balance these sort of complex, you know, binding energies with properties like PK solubility, drug absorption. And so I think that’s a place where modeling really, you know, can have a big impact here is sort of how do you balance these properties? And I think if you looked at a lot of the topics of of people talk about the drugs that were sort of at that transition from preclinical to clinical, those are really the challenges that they were wrestling with, which is things that improved the glue effect often had, negative impacts and other aspects and figuring out really how to balance those. And so I think that just one reflects the majority of the field as a lot more molecules moving to clinic, which is very exciting, but also that they’re having to tackle that next, round of challenges.
Absolutely. And applied by the bi applied biomass team. You guys are QSP quantitative systems pharmacology experts, can you talk about how ABM is using some of your QSP technology for this specific problem of molecular glues?
Yeah. So some of it’s around simulating the primary pharmacology. So really just looking at if you have to trade off, you know, half life or absorption or solubility, for binding potency, what are the optimal places to trade off there so that you get the best possible molecules.
The other is starting to think about now in clinical design and dose regimen design. And really understanding, you know, these molecules don’t just stick things together, but they target them to be degraded. You have this extended pharmacology of the resynthesis of your target over time. And really using that to understand how best to deploy these drives and how to sequence them so you have successful clinical trials. So I think it’s really bringing all of that together into one coherent picture. And allowing teams to kind of make the best decisions given, you know, the various tools that they have, to make adjustments.
Absolutely. And it sounds like you’re optimizing all these different parameters, like understanding structure activity relationship, but also, you know, having reasonable PK. It seems like these would be very long acting drugs since you have to both synthesize the the proteins that they’re degrading.
Yeah. I know that that’s exactly right. And and so I think these are generally people are going for oral daily delivery.
But, you know, the proteins themselves may resynthesize on the time scale of, you know, hours to days. And so I think people are also thinking about things like drug holidays, and do you give a dose every day? Or, you know, it’s the reason why twice daily dosing might be preferable, both from an efficacy perspective, but I think like all the these drugs that target intracellular targets. Selectivity is a big challenge because the same targets exist in many different cell types, some of which you may not want to target.
It’s so understanding whether there’s room to improve therapeutic index through things like the selection of dosing. You know, it’s another feature where, you know, now we’re talking about simulating the pharmacology, but the sort of downstream biology of the target and what happens after that. And so in that way, it’s very similar to the way we employed QSP in other modalities, it is really connecting it all the way back to the properties of the glue so that we could sort of really tell the sort of start to finish story and understand how the parameters level really have impact.
Fantastic. Well, Josh, it was a pleasure talking to you today.
Oh, thank you.
And, if you’d like to learn more about what Josh and his team are doing, please visit them at the Applied Biomath website. I’m Suzanne Minton, You’ve been watching Certara Talks. I’ll see you next time.