Unlocking Chemical Space: How WuXi AppTec Leverages DEL to Advance Drug Discovery

By adapting established reactions and introducing new molecular scaffolds into DNA-Encoded Library (DEL) systems, WuXi AppTec expands the chemical space available for molecular exploration, enabling clients to advance drug discovery.

DEL Innovation Expands Chemical Space

Over the past several decades, advances in technologies such as high-throughput screening (HTS) and DEL have expanded the scope of drug discovery. As the field strives to explore broader regions of chemical space, expanding molecular diversity has become a central focus.

As the industry seeks to explore broader regions of chemical space, team in WuXi Biology, a business unit of WuXi AppTec, continues to expand the capabilities of DEL-based discovery through the development of compound libraries, DNA-compatible reactions, and enabling technologies.

Since its introduction in 1992, DEL has become an important technology for early drug discovery. By attaching a unique DNA tag to each compound, researchers can screen billions of molecules simultaneously against a biological target and rapidly identify potential binders through reading the tag.

However, the value of DEL is not determined solely by library size. The diversity of molecular structures contained within those libraries is equally important. Even extremely large libraries may repeatedly sample similar regions of chemical space if the underlying chemistry remains limited.

As a result, introducing novel chemical scaffolds and expanding the range of reactions compatible with DEL have become key challenges across the industry.

Adapt Classical Chemistry for Modern Drug Discovery Platforms

Many classical chemical reactions predate modern drug discovery platforms. Now, WuXi Biology bridges this gap by adapting classical chemistry for compatibility with contemporary screening technologies.

One example is the Ugi reaction, first discovered by chemist Ivar Ugi in 1958. Unlike traditional stepwise synthesis approaches, the Ugi reaction enables multiple building blocks to be assembled into a complex molecule within a single reaction process.

Because different reaction components can be readily exchanged, the Ugi reaction offers an efficient way to generate structurally diverse molecules and has become an important tool for combinatorial chemistry and compound library construction.

Despite these advantages, the reaction has faced limitations in DEL applications because traditional Ugi chemistry relies on isocyanides and reaction conditions that are not always readily transferable to DEL systems.

This created an opportunity to revisit a well-established reaction through the lens of modern drug discovery needs.

Develop a New DNA-Compatible Strategy

To further expand the chemical space accessible through DEL, the WuXi Biology team developed a new Ugi-type strategy that enables the benefits of Ugi chemistry to be applied within DEL workflows.

The research team explored trimethylsilyl cyanide (TMSCN) as an alternative reagent capable of participating in Ugi-type transformations under mild aqueous conditions.

The resulting reaction system addressed several practical limitations associated with conventional Ugi chemistry while enabling the generation of fused imidazopyridine scaffolds, a class of structures that has attracted considerable interest due to its presence in approved therapies and pipelines across oncology, inflammation, and central nervous system disorders.

Importantly, the reaction conditions preserved the integrity of encoded molecules throughout the process, providing a foundation for practical application within DEL systems.

The researchers further demonstrated a workflow that connected Ugi-type chemistry, downstream modification, and tag incorporation, highlighting the potential for integration into real-world DEL library construction processes.

Expand the Capabilities of DEL-Based Drug Discovery

Building on years of platform development, WuXi Biology continues to expand DEL-based drug discovery by developing new libraries, introducing novel scaffold-generating chemistry, and broadening the range of molecular structures that can be explored through DEL.

Since establishing its DEL platform in 2018, WuXi Biology has built more than 1,400 DEL libraries containing over 1.1 trillion encoded molecules. The team has also developed more than 100 DNA-compatible reactions that support the introduction of novel chemical scaffolds and continued expansion of accessible chemical space.

Today, the DEL platform supports discovery efforts across a growing range of applications. Beyond traditional small-molecule screening, DEL is increasingly being applied to emerging areas such as RNA-targeted discovery and bifunctional molecule research.

As part of WuXi Biology’s broader discovery capabilities, DEL is integrated with technologies such as HTS and fragment screening to provide a comprehensive toolkit, enabling clients to efficiently identify and advance promising leads for drug discovery programs.

Key Takeaways

• WuXi AppTec expands chemical space for drug discovery through continuous innovation in DEL technologies.
• The team at WuXi Biology, a business unit of WuXi AppTec, developed a novel Ugi-type reaction strategy that enables structurally diverse scaffolds to be incorporated into DEL workflows, translating classical reactions into practical tools for modern drug discovery platforms.
• Since establishing its DEL platform in 2018, WuXi Biology has established more than 1,400 DEL libraries containing over 1.1 trillion encoded molecules to support early-stage drug discovery.
• WuXi Biology has developed more than 100 DNA-compatible reactions to expand the range of chemical transformations available for DEL applications.  
• WuXi Biology integrates DEL with HTS and fragment screening, supporting emerging applications such as RNA-targeted discovery and bifunctional molecule research.