同行致远 | 靶向“不可成药”靶点，PROTAC®如何加速走向临床？| Bilingual

编者按：靶向蛋白降解（TPD）技术通过“清除”病理蛋白，突破了传统小分子药物依赖活性位点的限制，为超过85%“不可成药”靶点提供了全新治疗策略。蛋白降解靶向嵌合体（PROTAC®）凭借其双配体结构和催化性机制，已成为药物研发前沿焦点之一。然而，其分子结构复杂，涉及双靶点识别、连接子调控与成药性优化等多个挑战，显著提高了药物从设计到临床的研发难度。面对这一复杂创新体系，药明康德早在TPD技术兴起之初便前瞻性布局，针对TPD开发构建起覆盖双功能DNA编码化合物库（DEL）筛选、连接子库构建、体内外生物活性评价及机制研究、DMPK评估与制剂优化的一体化赋能平台，助力全球合作伙伴高效推进PROTAC®药物从早期发现到临床试验阶段。本文将介绍药明康德如何通过平台化技术能力支持靶向蛋白降解药物开发，为新机制药物加速落地提供坚实支撑。

CRDMO: Targeting the Undruggable, How WuXi AppTec is Advancing PROTAC® Translation

Targeted protein degradation (TPD) technology offers a novel approach to eliminate pathogenic proteins, enabling access to over 85% of previously “undruggable” targets. However, TPD has challenges. Take proteolysis-targeting chimera (PROTAC®) as an example. These large, bifunctional molecules face unique development challenges such as dual-target recognition, linker design, and druggability optimization. Recognizing these complexities, WuXi AppTec has built an integrated platform for TPD research and development, supporting global partners from early discovery to clinical stages. 

From Inhibition to Degradation: A New Pathway in Drug Discovery

For decades, small molecules have been central to drug discovery efforts due to their oral availability and ease of synthesis. However, their reliance on binding to well-defined active sites limits their reach and leaves many disease-related target proteins “undruggable.” They also require continuous binding to be effective and typically do not eliminate the target, potentially reducing their overall impact on the disease.

TPD has emerged as a powerful strategy to overcome these limitations by eliminating, rather than merely inhibiting, pathogenic proteins. At the forefront of this approach are PROTAC®s —bifunctional molecules designed to simultaneously bind a protein of interest (POI) and an E3 ubiquitin ligase. By bringing these components into proximity, PROTAC®s trigger the ubiquitination and subsequent degradation of the target protein via the cell’s ubiquitin-proteasome system.

Since entering clinical evaluation in 2019, more than 30 PROTAC® candidates have advanced into clinical trials across a range of diseases, including cancer, autoimmune and neurological disorders, cardiovascular conditions, and viral infections. Unlike small molecules, PROTAC®s do not require high-affinity binding to an active site; instead, they act catalytically—once a target protein is degraded, the PROTAC® molecule is released and can initiate additional degradation cycles. This event-driven mechanism can enhance potency, lower dosing frequency, and potentially improve safety profiles by reducing off-target effects.

However, the development of PROTAC®s presents distinct challenges, as these bifunctional molecules must recognize both the POI and the E3 ubiquitin ligase while achieving stable protein complex formation. Additionally, their relatively larger molecular size—typically around 750 Da—can hinder solubility, cell permeability, and bioavailability, often requiring tailored design strategies and specialized formulations to ensure effective drug-like properties.

Starting with Bifunctional Molecule Discovery

To navigate these complexities, especially the need for dual-target recognition, scientists have turned to high-throughput approaches like DNA-encoded library (DEL) technology to accelerate PROTAC® discovery programs. DEL platforms enable the rapid construction and screening of large bifunctional libraries by fixing one ligand—either for the POI or the E3 ligase—while varying the other ligand and the linker. WuXi AppTec has developed DEL libraries comprising over 4 billion bifunctional molecules with diverse conjugation patterns, including libraries built around well-characterized ligands for CRBN and VHL, two of the most widely used E3 ligases in PROTAC® design.

In addition to ligand diversity, the design of the linker that connects the two binding components of a PROTAC® is equally critical. A successful PROTAC® must not only bind to both the POI and the E3 ligase, but also bring them into close and stable proximity to trigger effective protein degradation. The linker plays a central role in this process and can also impact key properties such as cellular uptake, solubility, and metabolic stability. To accelerate the identification and optimization of functional PROTAC®s, WuXi AppTec has developed a collection of over 1,000 unique linkers and maintains more than 50 frequently used options, enabling flexible and efficient fine-tuning of molecular designs.

Expanding on these efforts, WuXi AppTec has further enhanced its discovery capabilities with a specialized DNA-encoded screening platform tailored for PROTAC®s: the one-bead-one-compound (OBOC) DEL. This innovative approach improves conventional methods by immobilizing individual bifunctional molecules on separate microbeads, enabling direct interaction with both the POI and E3 ligase during screening. Molecules that successfully bring the two proteins together can be readily identified and efficiently isolated for follow-up studies, streamlining the progression from initial screening to downstream validation.

An Integrated Approach to Accelerate PROTAC® Development

While advanced screening technologies enable the rapid identification of potential PROTAC® candidates, this is only the beginning. Turning a hit into a viable drug requires systematic and integrated follow-up development. WuXi AppTec supports this continuum through its comprehensive R&D platform, guiding PROTAC® programs from structural validation and mechanism-of-action studies to DMPK evaluation and formulation optimization. The company’s research infrastructure is equipped to confirm protein complex formation and target degradation, while dedicated chemists, DMPK and formulation teams address key challenges such as solubility, absorption, and metabolic stability—helping to improve drug-like properties and accelerate progress toward the clinic.

To date, WuXi AppTec has successfully delivered more than 90,000 targeted protein degraders, spanning key stages from target identification to mechanism validation. Leveraging its fully integrated platform from discovery to clinical development, WuXi AppTec is accelerating the advancement of targeted protein degradation technologies—empowering partners worldwide and moving closer to its vision that "every drug can be made and every disease can be treated."

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