CRDMO: From Concept to IND, How WuXi AppTec Supports Targeted Protein Degraders Development in 12 Months

Targeted protein degraders (TPDs) offer a novel therapeutic approach by leveraging the body’s own protein degradation systems to eliminate disease-associated target proteins. This strategy opens new avenues for addressing previously “undruggable” targets.

When this technology was still in its infancy, WuXi AppTec began building relevant capabilities. Since then, we have established a comprehensive, integrated platform encompassing discovery, synthesis, purification, analysis, and testing. To date, this platform has supported the development of more than 120 TPD molecules, with over 20 advancing to clinical stages.

Several years ago, a biotech company developing a PROTAC® (proteolysis-targeting chimera) candidate faced synthetic challenges and turned to WuXi STA for support. The goal was to complete the production of drug substance and clinical trial material production within 14 months to support an IND filing and first-in-human trial. However, the original synthesis route involved 24 steps and yielded only 0.3%. Crystallization and purification proved difficult due to the compound’s unique structure.

Compounding the challenge, the candidate’s high molecular weight and poor solubility resulted in oral bioavailability of just 0.9%. Moreover, three steps in the synthesis relied on a palladium (Pd) catalyst, raising safety concerns and increasing production costs.

To resolve these issues, WuXi STA’s process chemistry, biocatalysis, and crystallization teams worked in concert to redesign the synthesis route, reducing the number of steps from 24 to 16 and replaced palladium with biocatalysts in two steps. To tackle crystallization bottlenecks, high-throughput crystallization screening identified suitable conditions that met both purity and yield requirements. These changes significantly improved the scalability and efficiency of the synthetic route while reducing costs.

Simultaneously, the formulation team addressed the low oral bioavailability by exploring a range of enabling technologies and ultimately selected spray-dried dispersion (SDD) to prepare a solid dosage form. SDD disperses poorly soluble compounds in an amorphous state within a polymer matrix and has been successfully used in several approved drugs. With this approach, the candidate’s oral bioavailability improved approximately 30-fold—supporting further clinical advancement.

Thanks to WuXi STA’s integrated CRDMO model, the following API and formulation development were advanced in parallel by multiple teams working seamlessly together. Ultimately, we delivered IND-enabling materials and clinical trial formulations within just 12 months—two months ahead of schedule.

As one of the industry’s leading platforms enabling targeted protein degradation, WuXi AppTec’s integrated services extend beyond PROTAC®®s to a wide array of bifunctional modalities, including:

• LYTACs (lysosome-targeting chimeras): for degrading extracellular or membrane proteins via lysosomes
• DACs (degrader-antibody conjugates): combining antibodies with protein degrades
• AUTACs (autophagy-targeting chimeras): small molecules inducing autophagic degradation
• RIBOTACs (ribonuclease-targeting chimeras): targeting and degrading specific RNA sequences

As targeted protein degradation continues to evolve, WuXi AppTec remains committed to leveraging its integrated CRDMO platform to empower the development of targeted protein degraders, helping partners translate scientific innovation into transformative medicines for patients around the world.

Find more information here.