How does WuXi AppTec's Direct-to-Biology (D2B) capability accelerate drug discovery?

WuXi AppTec has built the Direct-to-Biology (D2B) system, which integrates years of expertise such as medicinal chemistry, high-throughput chemistry, high-throughput screening, and computer-aided drug design into a continuous workflow. With the D2B capability, the design-synthesis-test cycle of a molecular glue program can be compressed from months to 2-3 weeks.

In recent years, molecular glues have emerged as a promising modality in drug discovery. Unlike conventional small molecules, molecular glues do not need to occupy binding pockets to function. This unique mechanism renders many previously "undruggable" targets accessible, but it also presents significant discovery challenges.

Because molecular glues typically work by inducing novel protein-protein interactions, their activities are difficult to predict directly. The discovery of candidate molecules still relies heavily on large-scale screening and iterative validation. In traditional drug discovery workflows, optimizing a molecular glue requires multiple rounds of “design-synthesis-testing”.

D2B Compresses the Design-Synthesis-Testing Cycle

The team in WuXi Biology, a business unit of WuXi AppTec, integrated capabilities accumulated over years to build the D2B system. With this model, when a client brings a molecular glue program to WuXi Biology, a design-synthesis-test cycle that used to take months can now be compressed to 2-3 weeks, significantly accelerating drug discovery.

"D2B is particularly powerful in hit expansion and hit-to-lead stages," said Dr. Wenji Su, Head of Discovery Biology Platform at WuXi AppTec. "At early stages, teams often need to assess hundreds to thousands of compounds, and D2B provides a more cost-effective way to accelerate these projects."

The D2B platform integrates miniaturized chemical synthesis and biological screening into a continuous workflow. To achieve this, the team combined the small-volume synthesis capabilities of the high-throughput chemistry team with the miniaturized bioassays and automation systems of the high-throughput screening team.

In the D2B model, chemical reactions are transferred into 384-well or 1536-well microplates. Each well acts as an independent miniaturized reaction unit, allowing a large number of chemical syntheses to run in parallel at very small volumes.

Once synthesis is completed, molecules can move directly into subsequent screening without going through traditional separation and purification steps, thereby accelerating the continuous design-synthesis-test cycle.

With the separation and purification step eliminated, impurities from the reaction system inevitably enter the biological testing stage. Ensuring that these impurities do not interfere with downstream assays became another key challenge in building the D2B platform.

Dr. Su explained that the team systematically optimized multiple aspects to address this challenge. For example, the team developed and optimized chemical reaction conditions to achieve higher conversion rates, while analyzing and selecting research materials to minimize impurity levels. Additionally, the team optimized assay conditions to evaluate the impact of different impurity levels and reaction conditions on downstream results.

Compared to traditional models, the D2B capability allows compounds to proceed from high-throughput screening to biological testing without "detours," shortening the overall cycle.

Expanding D2B Applications to New Modalities

As drug discovery faces increasingly complex novel molecular modalities, WuXi Biology’s D2B platform is also enabling more efficient early discovery and optimization. "In terms of applicable modalities, D2B is mostly suitable for TPD discovery, molecular glue, peptide, and conjugates including ADC, AOC, and others," Dr. Su noted, "Many of these molecules require extensive combinatorial studies at the beginning of projects, and D2B provides a more cost-effective way to accelerate these projects.”

Beyond the molecular glue example mentioned earlier, WuXi Biology's D2B capability has also been applied to the early discovery and optimization of other complex molecules.

In one case, a client advancing a TPD program encountered a typical cell membrane permeability bottleneck. These compounds have large molecular weights and high polarity, making cell membrane permeability an inherent challenge. Although candidate molecules showed ideal in vitro target binding, their cellular activity remained limited.

When the program encountered a bottleneck, the client approached WuXi AppTec. Based on an analysis of the client's molecular structures and target information, the WuXi Biology team leveraged D2B's high-throughput combinatorial chemistry capabilities to complete the design, synthesis, and testing of 2,000 molecules within one month. This provided new ideas for subsequent optimization and moved the program into further iteration.

The value of D2B also extends to exploring broader chemical space in early drug discovery. A client initiated a screening campaign against a difficult-to-drug target, but found that existing commercial compound libraries could not meet the project's needs. Rather than relying on the limited potential of off-the-shelf compounds, the client wanted to rapidly build customized compound libraries based on target characteristics to increase the probability of hit finding.

Using D2B's high-throughput combinatorial chemistry capabilities, the WuXi Biology team designed and synthesized more than 200,000 compounds within two months while simultaneously conducting screening. By significantly expanding the chemical space, the project obtained more potentially active molecules and notably increased the success rate of hit discovery.

The Next Frontier for D2B: Expanding Reaction Types

As drug discovery continues to expand into new targets, mechanisms, and molecular modalities, the need for speed and breadth in exploring chemical space keeps growing. Against this backdrop, the D2B platform itself is continuously evolving to meet more diverse demands.

Dr. Su noted that the variety of reaction types is a key factor defining the boundaries of the D2B capability. Since only a limited set of chemical reactions can be directly adapted to miniaturized systems, the team is continuously developing and optimizing reaction conditions to enable more commonly used reactions to be compatible with the D2B model.

To date, the team has developed multiple reaction types commonly used in medicinal chemistry projects, including coupling reactions and amide bond formation, and continues to explore new reactions to incorporate into the D2B workflow.

At the same time, the team is continuously expanding the chemical building block resources available for D2B projects. Leveraging the building block library accumulated over the years, the team is further expanding the chemical space that the platform can cover.

As drug discovery moves toward complex molecules and challenging targets, the D2B platform is expected to play an important role. As part of WuXi AppTec's integrated drug discovery capability system, D2B is creating synergies with multiple technology platforms, enabling clients to transform scientific ideas into verifiable results more efficiently.

Key Takeaways

• Team in WuXi Biology, a business unit of WuXi AppTec, integrated capabilities accumulated over years such as medicinal chemistry, high-throughput chemistry, high-throughput screening, and computer-aided drug design into a continuous workflow, establishing the D2B system.
• By integrating miniaturized synthesis and screening in microplates, WuXi Biology’s D2B platform compresses the design-synthesis-test cycle of a molecular glue program from months to 2-3 weeks.
• WuXi Biology’s D2B platform has been validated across complex molecular modalities. The platform has helped clients complete the synthesis and testing of thousands of molecules in weeks, addressing challenges such as cell permeability.
• In a case study, team in WuXi Biology designed and synthesized over 200,000 compounds in two months for a difficult-to-drug target, significantly expanding chemical space and increasing hit discovery success rates.
• WuXi AppTec is systematically developing more compatible reactions and building block libraries to support broader discovery needs.