Discovering Druggable Targets
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We recently spoke to Dr Kilian V. M. Huber from the Structural Genomics Consortium & Target Discovery Institute, University of Oxford, to find out – ‘What makes a good target?’. Kilian touches on the research being conducted at the Target Discovery Institute, the methods used to identify and validate drug targets, and the challenges faced by drug discovery researchers when identifying and validating targets.
Laura Lansdowne (LL): What makes a good drug target? How do you come up with a good target?
Kilian Huber (KH): A good drug target needs to be relevant to the disease phenotype and should be amenable to therapeutic modulation. At the same time, you need to have a good therapeutic window to assure that any therapeutic modality aimed at the target will not cause side effects by disrupting the physiological function of the target in healthy tissue. There is not one single approach that will deliver a good target on demand, but most people would probably agree that potential starting points can emerge from e.g. genome sequencing studies, genomic screens, phenotypic screening and existing drugs.
LL: Could you tell me more about your area of research and the research being conducted at the Target Discovery Institute?
KH: Our interest is very much focused on how chemistry can be used to study biology and help identify and validate novel drug targets. This includes interdisciplinary approaches to elucidate the mechanism of action of drugs and compounds with interesting phenotypes as well as the development of small molecule tool compounds, so-called chemical probes, that enable the investigation of the function of a protein in a cellular context. In short, we want to understand better how drugs and other bioactive compounds work and develop tools that enable an assessment of a potential target’s function and properties in both disease and physiological context. The Target Discovery Institute in Oxford comprises a number of different groups with complementary individual expertise in various areas relevant to drug discovery such as cell biology, protein biochemistry, chemistry, screening, proteomics, and pharmacology. By bringing all these scientists together in one institute, we hope to be able to identify and develop new targets for cancer, inflammatory and neurodegenerative disorders in a more efficient way.
LL: Could you touch on the importance of target identification in the different drug discovery approaches? (e.g. phenotypic screening vs. target-based screening)
KH: In principle, there is no regulatory requirement to know the molecular target of a drug or clinical candidate since all that matters in the end is that a drug is safe and efficacious. In fact, there are several approved drugs for which the mechanism-of-action is unknown. However, the drug development process is obviously greatly facilitated if the target is known since this enables rational design of new molecules with improved potency and safety profiles. Therefore, ideally you would be able to 'switch' from phenotypic screening to a target-based approach once you have confirmed and validated the hits from the former. For target-based screening, target identification can be achieved through sequencing studies, functional genomic screens or chemical probes. Ideally, you would want to be able to tick all those boxes before you embark on a new discovery programme.
LL: What methods can be used to identify and validate drug targets and how well are they working?
KH: There are many different ways for both. As mentioned above, the identification of mutations in disease tissue by genomic sequencing can point to genes or proteins whose altered function may be causing the disease phenotype. Functional genomic screens such as CRISPR-based gain- or loss-function screens can reveal candidates for target selection. Targets can also emerge from phenotypic screens or existing drugs. An example of the latter are the sulfonylureas that are used for the treatment of Type 2 diabetes which are based on antibacterial sulfonamides that coincidentally were found to lower blood sugar levels. For target validation, common approaches include genetic approaches such as knockout and overexpression, and transgenic animal models. If there are naturally occurring activating or suppressing mutations for your target of interest and the phenotype is in line with expectations this is also sometimes referred to as ‘validated by nature’.
A major focus of our work is on the development of chemical probes for target validation. These are small molecule tool compounds to study the phenotypic effects of e.g. inhibiting a given protein target in a cell or other model system. If a chemical probe exhibits the phenotype you are looking for, ideally even in an in vivo model, it can be an excellent starting point for a drug discovery programme. However, it’s important to keep in mind that the ultimate validation is still if modulation of the target turns out be effective and safe in a patient.
LL: What is your approach to developing new drugs?
KH: I don’t think it would be correct to say that we are actually developing drugs ourselves. Our aim is to enable and accelerate the drug discovery process by helping to find novel targets and de-risk them by providing tools for target validation. Being part of the SGC Open Science Consortium, we believe that it is crucial to share results and reagents with the community in a timely and unrestricted fashion, that is allowing people to use our reagents without having to wait for a publication or worry about potential intellectual property issues. We hope that by doing so we will reduce duplication of efforts and costs, and enable experts across all disciplines to find new targets faster and in a more efficient way. In other words, we want to get the best people from industry and academia together to bring new medicines to the patients as quickly as possible. In analogy to the internet’s public domain idea we like to refer to this concept as ‘scientific crowdsourcing’. We think it is important to include patients in this effort as well; it is easy to forget about the human being as a whole as we tend to think of diseases as technical problems and some of the ideas we have may actually not give the patients and their families what they need. This open approach hopefully will also make drugs more affordable.
LL: What are the challenges when it comes to identifying and validating targets?
KH: As in essence the only real validation is if a drug turns out to be safe and efficacious in a patient, a major challenge is that many targets fail late in the clinic, several years after initiation of the project. Thus, we have to improve on our ability to identify promising targets early on and open science and sharing of data may help in this regard. I think this is also particularly relevant in the context of the recent discussion how artificial intelligence (AI) and related approaches could help us in becoming better at finding new targets. As for target identification there isn’t one simple way to do it. Apart from the approaches mentioned above, I think it’s also important to continue studying fundamental biology as for instance we still know very little about huge parts of the human proteome.
Dr Kilian V. M. Huber was speaking to Laura Elizabeth Lansdowne, Science Writer for Technology Networks.