Beyond DNA-Encoded Library Screening: How Integrated Services Improve the Outcome of the Drug Discovery Program
As the industry leader in DNA-encoded library (DEL) technology, X-Chem’s core business has been the hunt for novel small molecule hits using our proprietary DEL discovery platform. The identification of a potent, developable hit is a crucial step in any drug discovery program. However, it is only one component in a complex and work-intensive process. The successful outcome of a discovery program depends on many factors: availability of high-quality and active protein samples, robust biochemical/biophysical assays to characterize compound activity, access to high-resolution protein structures, computational chemistry, medicinal chemistry expertise and more. Access to high-quality proteins and assays, better libraries, insights into ligand-protein interactions and mechanism of action increase the odds for success. And together, they act as door openers to high-hanging-fruit targets that previously were typically considered out of reach/undruggable. The use of sophisticated technologies and the relevant scientific know-how are needed throughout the process — upstream and downstream of the hit identification. But finding and choosing the right providers for the different types of services, let alone managing them all, can be challenging and time consuming.
Expanding Beyond DEL
X-Chem is working with other service providers to access world-class capabilities and expertise. We look for partners with the right know-how to augment, support or build on our core expertise. By pursuing a networked approach we can combine services from best-in-class providers and deliver excellence across disciplines, leading to truly differentiated outcomes. Our clients gain access to the experts, with the ease of a single point of contact, smooth workflows, ease of communication and simplified project management. This leads to higher-quality service and, consequently, more successful outcomes.
Taking DEL Hits to the Next Level: X-Chem’s New Medicinal Chemistry Unit (formerly IntelliSyn)
Most of X-Chem’s clients look for novel, potent hits from a DEL screen. What’s next? The DEL hits serve as the starting point for a hit expansion and optimization program. Pharma companies do much of this medicinal chemistry work in-house or outsource it within a preexisting infrastructure of providers. Many biotech companies do not have all relevant capability in-house or an established infrastructure and therefore look for external providers to lead the hit optimization process. In January 2021 X-Chem acquired IntelliSyn, a Montreal-based medicinal chemistry company. IntelliSyn’s work typically starts with a small molecule hit or lead — which is precisely the output from X-Chem’s DEL screen. Moreover, the leadership in Montreal have a strong track record of developing hits into clinical candidates. Their delivery of 12 clinical candidates reflects the dedication to excellence in medicinal chemistry that we were looking for to build on our hit-discovery expertise. With IntelliSyn now a fully integrated part of X-Chem, we offer full chemistry services from hit identification all the way to candidate — providing an easy solution for our clients to meet their small molecule discovery needs.
The X-Chem and Proteros Partnership
In October 2020 X-Chem and Proteros Biostructures entered into a partnership with the goal to better support our respective clients. We had previously worked with Proteros, a world leader in protein science and structural biology, based in Munich, Germany. In previous projects we experienced first-hand the high quality of their protein samples and their expertise in structural biology. DEL clients frequently look to X-Chem for sources of high-quality proteins. Similarly, clients of Proteros frequently look for small molecules to target their protein. We formalized our relationship with a cross-referencing arrangement and now work together in offering our respective services. Clients with an interest in DEL discovery appreciate the ease of access to high-quality protein prepared by Proteros to meet X-Chem’s quality requirements. Off-DNA synthesis of DEL hit compounds are provided by X-Chem to Proteros for biophysical hit confirmation/cross-validation and subsequent high-resolution structural validation for a complete elucidation of compound binding mode. Following the identification of a hit, the client can continue to work with X-Chem on hit-to-candidate optimization — benefiting from the chemistry expertise provided by our IntelliSyn colleagues in Montreal. Advanced hits can also be further characterized biophysically and structurally enabled through X-ray crystallography or cryo-EM by Proteros. X-Chem’s screening and chemistry expertise is matched perfectly with Proteros’ structural biology and biophysics expertise.
An Example: The Arbutus — Proteros — X-Chem Partnership
In April 2021 we announced a three-way-collaboration between Proteros, Arbutus Biopharma and X-Chem regarding the discovery of novel inhibitors targeting the SARS-CoV-2 nsp5 main protease (Mpro), an important protein in the life cycle of COVID-19 and other coronaviruses. The agreement was designed to accelerate the development of pan-coronavirus agents to treat COVID-19 and potential future coronavirus outbreaks.
X-Chem and Proteros had begun to explore targeting Mpro just a few months before. Enter Arbutus: The company, an expert in the development of antiviral drugs, was interested in pursuing a DEL approach to Mpro and quickly became interested in this integrated solution. The resulting collaboration brings together Arbutus’ expertise in the discovery and development of antiviral agents with X-Chem’s industry leading DNA-encoded library (DEL) technology and medicinal chemistry expertise, and Proteros’ protein sciences, biophysics and structural biology capabilities. Arbutus, as the party with the rights to advance the fruits of the partnership into the clinic, was attracted to the complementarity between their own expertise and the respective capabilities of Proteros and X-Chem.
It is undoubtedly an exciting time for small molecule drug discovery: As the technological prowess in dissecting the underlying molecular mechanisms of disease processes improves, as our ability to survey vast chemical space to probe molecular folds grows, discovery research can tackle more disease targets in new and previously inaccessible ways. Success will be found by those who are most effective and knowledgeable in combining the right tools and expertise — through integration of capabilities and services and through collaboration with the right partners.
Steffen Helmling is X-Chem’s chief business officer. He has worked in drug discovery platforms and early stage drug research for over 20 years, most of them in business development and licensing.
X-Chem’s primary mission has always been to leverage the world’s leading drug discovery platform to help create molecules that will...
DNA-encoded library (DEL) selections typically use affinity pulldown to enrich compounds that bind targets of interest. While it is highly...