Examining the future of Small-Molecule Chimeras: An Interview with Guido Koch of Amphilix

PF: It’s great to have you here today – could you tell us a bit more about your background and, ultimately, what led to your founding of Amphilix?

GK: I am a chemist by training, having studied at ETH in Zurich, and after my PhD I opted to do a post-doc at CalTech. Chemical biology was one of my driving passions, particularly the intersection of chemistry and the discovery and production of pharmaceuticals. This is what drove me to start my career in a classical pharmaceutical research environment with Novartis – where I spent 22 years, eventually making my way to the level of Director in Global Discovery Chemistry. My focus was primarily on new modalities and molecules that are difficult to make; it was a highly exhilarating experience and I consider it a privilege to have had the opportunity to work on so many projects that led to clinical candidates. With my combined learning and my passion for connecting business with science, it seemed only natural to attempt a new endeavour in a business environment – which I did by moving into a COO position for Topadur Pharma, helping to advance the company from a preclinical stage. This was a very illuminating experience – the difference between big pharma and new companies can be quite significant. Such differences were more pronounced on the investor-facing and business side of things – which are not necessarily responsibilities researchers have themselves in bigger companies. Through these formative experiences, as well as my early passion for the discovery of new modalities, the founding of Amphilix seemed like the culmination of this natural progression. Our co-founders are equally as passionate – including ex-Novartis Kevin McAllister and the ETH spin-off chemistry company, Spirochem.

PF: Small molecule chimeras, which are typically dimeric, are a rather new technology that is expected to open up new avenues in drug discovery – what advantages do you feel they bring to the table? Do they open up new targets that were previously untargetable?

GK: This is an excellent question – the whole field of small molecule chimeras was actually kickstarted by Proteolysis targeting chimeras (PROTACs), which is a modality for targeted protein degradation. Chimeras focus on bringing two biological targets together, which usually do not interact with each other on their own – the technology we use to connect them is therefore critical. Beyond PROTACs, we can use technologies for specific target sites of interest (e.g. cell types or disease tissues), introducing greater elements of precision in how we deliver therapies. We have seen similar concepts being employed with other technologies, such as antibody-drug conjugates. We also see a revolution in the field of radiotherapeutics, where bifunctional molecules are integrating a targeting element with a radiation agent.

PF: Proteolysis targeting chimeras, often called PROTACs, are perhaps the most common modality for dimeric chimeras – do you feel any other technologies, such as RNA-Degrading Ribonuclease Targeting Chimeras (RIBOTACs), may hold equal promise?

GK: I think we are still in the very early stages as we have only seen some PROTACs make it into the clinic so far. I expect we will learn a lot about the pros and cons of small chimeras in a clinical stage from PROTACs, but I am confident that bifunctional molecules will not be limited to the PROTAC world. There will be a lot more to come, including RIBOTACs as well as some of the modalities I mentioned earlier. Beyond that, I think small molecule chimeras have done great things in pushing the horizons of medicinal chemistry beyond traditional boundaries, and improving how we design new drugs in general – particularly in making larger molecules more drug-like and orally bioavailable.

PF: Drawing on that last observation on bioavailability, what limitations do you expect to encounter as Amphilix progresses further in the field? What are the chief obstacles between in vitro success for small molecule chimeras and turning them into an oral pill?

GK: This is a key question to solve in the field – while theoretical possibilities abound, we need to remain realistic regarding the limitations on the size of molecules, and the type of targets that we can address. The latter remains critical, particularly as we discover which molecules can reach different tissues, such as brain targets, and how to optimize such deliveries. Working with more advanced drug formulation technologies will definitely push the limits of what we can do as well. The field is still at an early stage where it is shifting boundaries, so it would be fair to say that we are still discovering what the limitations are. The reality check will become more apparent as we follow up PROTAC candidates making their way through the clinic. However, the tools that are available to us, such as improvements in computational design – and computational throughput in general, leave me optimistic for next generation bifunctional molecules.

PF: Small-molecule chimeras are closely associated with the field of oncology – do you feel they will make their biggest impact there, or are there other fields that you feel equally excited about?

GK: I think this is actually a very common theme – many new modalities, particularly for new drug targets, are first seen making their way in oncology. This is due to the fact that oncology offers one of the fastest paths into clinical proof of concept, and the insights provided from early oncology trials can also assist in bringing these modalities to patients for other diseases; I see no obvious reason for chimeras to remain limited to oncology.

PF: Is there a role for AI in the discovery of new chimeric drug candidates? Do you think wider adoption of artificial intelligence, and advancements in the capabilities of such intelligence, will be a necessity for improvements in small molecule chimeras?

GK: This is something we are extremely interested in at Amphilix – we are currently setting up a collaboration with an AI company. Designing a new cell or tissue targeting drug is a very data-intensive process, and requires a lot of computational power. Thus, I believe that AI can efficiently support the target selection and prioritisation process. The application of AI in drug discovery has the potential to revolutionize our science throughout multiple fields by removing the brakes on some of the biggest bottlenecks in their development.

PF: You will be attending our Medical Chemistry Strategy Meeting in London this year – where you will be speaking about the role of AI in Drug Discovery. We will of course be delighted to host you. Are you also looking forward to meeting with colleagues and sharing your own insights?

GK: Oh, absolutely. I believe this is one of the biggest pleasures of working in science – the common and free exchange of ideas and perspectives. I think the discourse is particularly more important in these evolving, new areas – such as AI in drug discovery. It helps to set the pace for new technologies in which we would like to invest and which we need to promote for the future of medicine.

José María De Uriarte Díaz, Head of Production, Proventa International

Nick Zoukas, Former Editor, PharmaFEATURES

No individual or organization can bring innovation and results alone in science; this has always been an accepted truth in the field, made more plain by the COVID-19 pandemic. Join Proventa International’s Medical Chemistry Strategy Meeting for Europe in London to hear about the latest developments in medical chemistry, speak to world-renowned experts, and perhaps even to find your next most productive collaboration.