Drug discovery is complex and the expertise it requires is vast. Matthew A. Clark, Chief Executive Officer, X-Chem, talks to Lu Rahman about the company’s experience of collaboration and how it enables innovation, flexibility and problem-solving.
Drug discovery is the most interdisciplinary of all scientific endeavours, says Clark. “To successfully discover and develop life-improving medicines, one must tap into deep expertise in such disparate fields as genetics, biochemistry, cellular biology, medicinal chemistry, synthetic chemistry, pharmacology, data science, translational research and many other disciplines. In addition, the scope of available data has exploded, which requires increasingly large-scale methods for taming and understanding information,” he explains.
This phenomenon has been referred to generally as the rise of ‘big data’. “The genomic revolution is the most obvious manifestation of this, but similar developments can be observed in the chemical sciences. Virtual libraries, screening databases and synthetic route prediction are examples of big data applied to chemistry,” he adds.
These factors, says Clark, make it difficult to assemble all the required expertise under one roof, let alone best-in-class capabilities. “Particularly for start-up companies, but even for large pharma, collaboration and partnership are necessary to access the best technologies and capabilities. Given the richness of the current information ecosystem, the days when a company could go it alone are likely over. Collaboration gives companies the flexibility to access the right tool for the right problem at the right time. Drug discovery becomes increasingly dependent on an expanding network of expert providers, forming new specific webs of collaboration to solve specific problems,” he adds.
X-Chem recently entered a research collaboration and license agreement with Genentech. Clark explains how excited X-Chem was about this. “Genentech has an outstanding track record of innovation and quality that dates back to its founding. Working together, we hope to make a real difference for cancer patients,” he says.
The roots of this collaboration were found in X-Chem’s DEL platform. “We applied our discovery platform to a high-interest oncology target. Tapping into our most innovative and high-quality libraries, we identified compelling novel chemistry that was of interest to Genentech. The program illustrated the power of our platform in addressing difficult drug discovery challenges. On this basis, we initiated a collaboration with Genentech to apply our platform to other difficult oncology targets that have been considered elusive or undruggable. The goal is to go after targets that have the potential to make a truly meaningful impact for patients.”
The key benefits of this collaboration are significant. If successful Clark believes this collaboration will demonstrate druggability and validation for a new family of oncology targets. “These are targets for which the industry does not currently have effective strategies to address, but that all available data show would be game changers for patients,” he adds. “Beside addressing these high-interest targets, our collaboration will demonstrate to the industry that our platform is the method of choice for addressing the difficult biological targets of the future.”
As part of the collaboration Genentech will be utilising X-Chem’s DNA-Encoded Library (DEL) technology. “X-Chem’s DEL platform is a leading method for quickly mining ultra-large chemical libraries that are exponentially larger than typical screening collections. Our DEL platform is founded on the premise that preparing, purifying and storing chemicals in the traditional paradigm is costly and slow. This is evidenced by the fact that humanity has only prepared less than 1% of the number of the compounds that could be readily prepared from available precursors using convenient chemical reactions,” explains Clark.
By attaching the products to DNA, compounds can be screened at small scale and as a mixture. “This allows us to prepare libraries that meaningfully sample the available chemical space, spanning billions of discrete structures. At the same time, we use our drug discovery expertise that ensure these libraries contain compounds that can be readily progressed into medicinal chemistry”. Clark feels that too many libraries in the DEL field comprise large molecular weight and highly lipophilic compounds that provide poor starting points for drug discovery. “We focus on physicochemical properties and atom economy to ensure the highest quality outputs. That said, we also maintain a set of macrocyclic and peptide libraries for addressing certain unique target classes,” he adds.
Clark explains that the DNA tag doesn’t just allow large libraries: “It allows us to screen these libraries using mixture-based affinity selection. The selection experiment is highly miniaturised, and it can be multiplexed to provide additional data around selectivity, potency and site and mechanism of action. Since the output of the selection experiment is analysed by DNA sequencing, we are able to take advantage of modern high-throughput sequencing technologies.”
A typical selection experiment can result in hundreds of millions of datapoints, giving a comprehensive view of the relevant chemical space, including emergent SAR.
“Of course, utilising such large data sets requires robust informatics tools. X-Chem’s suite of bioinformatic analysis tools allows us to effectively assess ultra-large data sets,” he adds.
X-Chem has entered into numerous drug discovery partnerships with pharmaceutical companies, established and early-stage biotechnology companies, as well as research institutes and universities resulting in the licensing of hundreds of novel hits and leads across many target classes and therapeutic areas. This collaborative approach suits the company and its work.
“X-Chem’s mission is to deploy its DEL platform as widely as possible so that we can positively impact human health. We do not pursue an internal drug discovery pipeline and we do not invest in the development of drugs. Instead, we are positioned as a partner in innovation for the biopharma industry. We believe that all researchers in this industry can benefit from access to ultra-large chemical libraries, whether they are academic researchers unlocking the disease biology of the future, or pharma scientists populating a pipeline of innovative medicines. Whatever the setting, access to high-quality small molecule modulators of biological function is a key to success,” explains Clark.
Over the years, X-Chem has worked with partners on projects spanning a range of therapy areas and target classes. “We have built up a huge database of historical screening data that helps us quickly assess new screening hits for historical behaviour,” Clark reveals. He believes this is a key and underappreciated element of the company’s success.
“Any medicinal chemist can tell you that promiscuous compounds are the surest way to waste precious resources. It is no different in the DEL area, so a large database of historical results is absolutely critical for identifying and filtering frequent hitter compounds. In addition, X-Chem has developed particular expertise in a number of target classes, including kinases, GPCRs, E3 ligases and protein-protein interactions.”
Covid-19 has affected the industry in many different ways. To advance drug discovery and development many companies have recognised the need for collaborative work during the pandemic. “I believe that COVID has definitely demonstrated that more flexibility and collaboration in drug discovery is not only possible, but quite powerful and attractive,” says Clark. “We’ve all seen and learned how remote working has transformed how we interact and conduct business. At the same time, the need for laboratory work and data generation remains undiminished, and limits the degree to which work-from-home can be implemented in our industry. Social distancing policies, shift work and varying local conditions present challenges that can slow down the production and analysis of data. It seems clear that a more distributed network of data providers can more easily respond to these challenges than a centralised research hub. Additionally, innovative processes that efficiently produce more data, whether by miniaturisation, automation or parallelisation, can greatly enhance flexibility.”
Clark acknowledges that X-Chem has been lucky. While its office staff have been working from home for almost a year, it has been able to maintain social distancing in its laboratories without losing pace of experimental science.
“It is a hallmark of the DEL platform that small teams can make big impact; a two-person team, within a socially distanced paradigm, can still generate a 10-million compound library in a reasonable time frame. A selection scientist can generate a 100-million point data set, or a biochemist can turn around several plates of SAR data, all within a light lab footprint. Of course, our informatics processing can be easily conducted remotely. We hope and expect that our partners have seen no slowdown in our ability to produce high quality science,” he reveals.
With his experience of collaboration and the benefits it can create commercially and scientifically, Clark has some valuable advice for drug discovery and development companies thinking about partnerships and how they can work to their best advantage. “My advice to a drug discovery company would be to articulate your differentiating internal capability, precisely define a scientifically informed discovery strategy and assemble a network of providers who have the expertise and the track record to deliver on that strategy. What are you the very best at, and who are the best who can help with the rest? In terms of lead generation, what is the logical starting place for your disease biology? Knowledge-based design? Phenotypic screening? If the target is very novel, a high quality DEL provider like X-Chem would be a good place to start,” he says.
Clark suggests identifying and assessing providers who can deliver on your precise lead generation strategy. “In lead generation, it is best to not be tempted by low-quality commodity providers. Quality in lead generation can pay dividends throughout optimisation and development, while poor starting points hamstring a project throughout its duration. The same assessment should be made for medicinal chemistry, DMPK/ADME, cell biology, toxicology, animal models, etc. If a single provider can perform in several of these areas, assess their expertise in each area on its own merits.”
He gives an example – not every synthetic chemistry provider can offer a high-quality DEL platform, nor can every protein production shop provide crystallography-grade protein. “At X-Chem, we have assembled a network of key capabilities, both internal and external, that can provide support from target ID through lead optimisation. With our recent acquisition of Intellisyn, we are now a leading medicinal chemistry provider in North America. This capability means that we can take the outputs from our DEL platform and quickly move them toward a lead compound and even a candidate. Externally, we bolster this capability through partnership with one of the world’s leading structural biology providers, Proteros. With our expanding network of partners and capabilities, X-Chem can be a true partner in innovation, helping our partners fill the drug discovery pipelines of the future.”
Volume 22, Issue 2 – Spring 2021
Clark is a world-recognised innovator and leader in the DNA-encoded library (DEL) field. He was part of X-Chem’s founding team and served as VP of chemistry and SVP of research prior to his appointment to the CEO position. He is a thought leader in the DEL space, with numerous patents and key DEL publications to his name.