A pool of no fewer than six thousand genes to search for ‘druggable targets’ ... this may sound pretty impressive, given the multitude of options to choose from for pharmacological research. “There’s already a lot. However, we did face limitations,” says Piet Wigerinck, Galapagos’ Chief Scientific Officer. “By only focusing on druggable targets, we would have to rely on public knowledge about proteins that may play a key role in a disease process. And in fact, our challenge is greater, as we focus on the development of drugs that can be taken as oral pills and that moreover need to display minimal side effects.”
The aim is to have a target pool closer to twenty thousand potential targets. “By following the science and with the aid of our ultra-precise target search mechanisms, we are expanding the horizon within which we operate. As such, we are well-placed to find the best targets in a larger haystack,” he adds.
Widening the lens: not the destination but looking at the entire journey
In the search for new medicines, Galapagos goes beyond the conventional approach of targeting proteins that are present at the site relevant for the disease, to explore instead the routes that proteins travel in a disease process. Piet Wigerinck says: “Instead of going for ‘druggable targets,’ we are shifting the focus to the so-called ‘disease pathways.’ We now look at the whole cascade of events in a body that can cause a disease. Individual proteins represent only a small part of a complex network, with feedback loops where multiple proteins interact. This new approach means we are no longer looking at just six thousand different genes, but instead we have expanded to no fewer than twenty thousand potentially interesting genes.”
Innovative target discovery
We use our own target discovery platform to discover whether a certain protein is suitable for interrupting a disease process. With the aid of a modified virus particle which is no longer able to reproduce itself in cells, such proteins can be disabled. It is thanks to the extensive understanding of certain disease processes, combined with the expanded new screening approach, that we are now able to search for more genes and thus increase our chances of finding innovative mechanisms. The primary question when assessing whether or not a drug target could lead to a successful new medicine remains: is this potential new mechanism of action indeed innovative? Can this new approach really make a difference in treating diseases for which there is not yet an adequate cure?
More targeted search
Piet Wigerinck explains that, while this new approach has indeed increased the size of the search pool, the screening process remains similar. “It is precisely by adopting a highly targeted search along the various disease pathways, that we are able to focus better on those genes that play a dominant role in the disease process. We are not starting from scratch; we already know the sections of the pathways where we can find interesting starting points.”
In addition to this search method, Galapagos is also adding two new ways of impacting the disease process: by inhibiting or rendering proteins harmless. Piet Wigerinck says, “In addition to small molecules that specifically inhibit the activity of a protein, we will also search for ways to block the production of a protein entirely. The ‘recipe’ for each protein is stored in our DNA. This must first be transferred to RNA, after which messenger RNA, or mRNA, places the actual building blocks for a protein in position. If we can block the latter process around the mRNA, using new small molecules, so-called oligonucleotides, the proteins in question are no longer produced and therefore do not need to be inhibited.”
In the past year, mRNA has become known to the public as a new way to develop vaccines against COVID-19. Piet Wigerinck emphasizes that “mRNA has now proven itself, just like oligonucleotides, as an effective starting point in pharmacology as well.” He adds that the longer-term ambition of Galapagos will be to develop oral drugs based on this modality.
Rendering proteins harmless
The second new approach to impact the disease process is based on proteolysis, or rather: the waste stream of proteins in a human cell. Piet Wigerinck says: “The so-called PROteolysis TArgeting Chimeras, or PROTACs for short, break down a protein, instead of inhibiting it. These PROTACs have already proven to be less susceptible to losing their treatment effect, compared to conventional drugs after prolonged use. Their pharmacological effectiveness in cell cultures was as much as 99% in various cases, where classic inhibition of proteins often does not exceed 90%.”
Building on this pharmacological advantage, the challenge remains around how PROTACs can be used in patients. Piet Wigerinck goes on to explain that “before a drug can be taken orally, a substance must be made water-soluble and it must be able to cross membranes in the body, not to mention all the other chemical requirements. For PROTACs, these requirements are more complex than for classic small molecules.” He adds “However, I think that these agents will potentially play an important role in regulating autoimmune diseases, among others.”
Turning ambition into reality
Galapagos has always looked at ways to enhance and accelerate drug discovery efforts. Today, we are doing so by adopting a new way of looking for interesting starting points and by exploring new approaches to inhibiting protein activity in a disease process. “Developing an innovative drug is by definition a long-term objective, nothing new here,” declares Piet Wigerinck. “The mere nature of what we do, the fact that our common understanding of human biology is evolving every day, that scientific discovery processes go through exponential leaps, all this makes our work not only very complex but a real test of our perseverance. Just consider that, statistically, in our industry only one in twelve targets ever reaches the finish line,” he adds, before concluding, “We aim to make our ambition a reality by evolving our research strategy. Ultimately, the mission we set ourselves is to meet the unfulfilled medical needs in inflammatory, fibrotic and kidney diseases.”