Research Partnership Aims To Advance Fragment-Based Cancer Drug Discovery

The concept of fragment-based drug discovery has been around since the 1980s, and it’s based on the idea that drugs can be viewed as consisting of fragment building blocks that are linked together. Biological targets are screened against small chemical fragment libraries using a variety of techniques including nuclear magnetic resonance, surface plasmon resonance and X-ray crystallography, and fragment binders can then be evolved into drugs. Compared with compounds identified using traditional high-throughput screening approaches, fragments are typically much lower molecular weight making them easier to manipulate and optimize. This is important since successful, orally bioavailable drugs tend to be smaller compounds.

Fragment-based drug discovery has been applied to develop drugs in many therapeutic areas including cancer. The very first drug to come out of fragment-based screening was the BRAF kinase inhibitor, vemurafenib, for late-stage melanoma, which was approved by the US Food and Drug Administration (FDA) in 2011. Fragment-based drug discovery allowed the drug to be fine-tuned to target a specific mutant form of BRAF, the V600E variant, which is the most frequent oncogenic point mutation observed to date. Currently, there are more than 50 compounds derived from fragment-based drug discovery in clinical trials, and a total of 7 FDA-approved drugs, which is testament to the success of this technique.

Historically, a bottleneck in fragment-based drug discovery has been the time it takes to identify fragment hits. Diamond Light Source has pioneered the use of X-ray crystallography for fragment screening by developing a state-of-the-art, proprietary technology platform called XChem, which has significantly accelerated timelines and transformed X-ray crystallography into a viable primary fragment screening method.

It’s now possible to screen a library of approximately 1,000 fragments at Diamond in 1 week – this would have conventionally taken months. The XChem pipeline streamlines the process from soaking protein crystals with fragments through to data collection, analysis and identifying binders. Furthermore, it provides exquisite atomic resolution detail about how fragments bind to the target protein, which is crucial to evolve fragments into drugs. XChem was exploited during the pandemic to develop potent Mpro inhibitors with antiviral activity in record time as part of the Covid Moonshot consortium. 

Cancer Research Horizons and our drug discovery site at Newcastle University already routinely access Diamond’s beamlines and XChem facility for fragment screening. This exciting new partnership will enhance our existing relationship to deliver improvements in throughput, running and analysis of these experiments.

Put simply, by leveraging our joint expertise and resources, this partnership will enable us to fast-track our drug discovery programs and help deliver new cancer treatments to patients faster.

There are more than 200 different types of cancer, and Cancer Research Horizons, as the innovation engine of Cancer Research UK, has a remit to develop therapeutics for cancers of unmet need. These are notoriously hard-to-treat cancers, and many are associated with a poorer prognosis. By tapping into our drug discovery capabilities, we can pinpoint proteins that are key drivers in cancer, and, through our partnership with Diamond Light Source, we’ll be able to identify chemical starting points targeting these proteins quicker to accelerate drug discovery.

Also, we’ll be able to screen targets that have historically been considered “undruggable” such as transcription factors. We can explore alternative mechanisms to impact the function of proteins and/or protein complexes, for example, by targeting allosteric sites remote from the catalytic core thereby modulating activity, or by targeting protein–protein interactions by identifying fragments that bind to protein interfaces.

As I mentioned earlier, a key challenge in fragment-based drug discovery is the speed at which fragment binders can be identified, and then followed up with atomic resolution structural data to reveal how they bind to the target protein. Using the fragment screening capabilities at Diamond we get to identify fragments that bind to a protein of interest and get detailed atomic-resolution structural information about how the fragments bind, at the same time. Furthermore, XChem can detect weakly binding fragments with low affinity. Such fragments would typically be missed using conventional fragment screening approaches but can represent valuable chemical starting points.

The ability to generate structural information for bound fragments is a critical component of any fragment-based drug discovery campaign as it guides medicinal chemistry efforts. XChem at Diamond will significantly enhance the efficiency of our fragment-based drug discovery programs. This progress will be further accelerated by gaining early access to proprietary developments to the XChem platform.

I’m excited to see what this partnership delivers in the cancer drug discovery space over the coming years. I believe that, as well as helping us to identify novel chemistry for cancer targets in our portfolio, it will help drive technological advancements at Diamond leading to further improvements to the XChem platform. We have ambitious plans to screen a number of novel cancer targets as part of this partnership. These targets will correspond to novel targets in our drug discovery portfolio and will enable us to fast-track the scientific breakthroughs from our research into patient benefit. In addition, this initiative will enhance the appeal of fragment screening as a hit finding strategy, and XChem, to our pharmaceutical and biotech partners, driving broader industry engagement.

We’re passionate about developing novel drugs to improve patient outcomes, and to reduce the time it takes to deliver these drugs from bench to bedside. Our goal is to deliver selective, potent drugs that specifically target the drivers of the disease. I strongly believe that our newly formed partnership with Diamond Light Source will help lead to Cancer Research Horizons developing better and safer cancer drugs.