从“抑制”到“降解”：药物研发的新路径

自20世纪中叶以来，小分子药物通过精准结合蛋白活性位点，有效抑制多种病理蛋白功能，极大推动了医学进步。然而，随着基因组学和蛋白组学的发展，研究发现约85%的蛋白缺乏可被传统小分子识别的“成药性”结合口袋，尤其是功能位点不明确的蛋白几乎无法介入干预，这一局限性也促使科学界不断探索新的成药机制。

正是在传统小分子面临这一挑战下，TPD策略应运而生。以PROTAC®为代表的新型分子不再依赖对蛋白功能的抑制，而是通过招募E3泛素连接酶，将目标蛋白（POI）标记并引导至蛋白酶体降解，从源头上阻断病理机制。由于PROTAC®分子不需与POI上特定的活性位点结合即可启动降解过程，使得诸如转录因子等传统上“难以成药”的靶点也成为可能的干预对象。此外，PROTAC®分子在完成POI降解后可被释放循环使用，这一机制不仅有望提升药效，还可能降低所需剂量，从而提高治疗的安全性。

靶向蛋白降解：从双功能分子筛选开始

尽管TPD策略为攻克“不可成药”靶点带来了全新可能，但要将其成功转化为临床可用的PROTAC®药物，仍需跨越一系列技术门槛。由于PROTAC®分子由分别结合POI与E3泛素连接酶的配体通过连接子连接而成，其结构复杂度远高于传统小分子，这也使得从分子设计到药物筛选的全过程更加繁复，对研发能力提出了更高要求。

面对PROTAC®分子结构复杂所带来药物筛选上的不易，科学家们引入创新技术以加速药物研发流程，其中DEL正是最具代表性的一项。DEL技术可构建规模达数百亿级的化合物库，每个小分子都通过共价方式连接一个独特的DNA条形码。在筛选过程中，能够与靶点结合的小分子被富集，附着其上的DNA标签经过扩增后用于识别对应的分子结构。由于每段DNA标签具有独特性，研究人员可据此快速追溯到原始化合物。凭借分子规模庞大、操作简便且不依赖昂贵仪器等优势，DEL技术在近年来被广泛应用于新药早期发现阶段，显著提升了筛选效率与成功率。

为应对PROTAC®药物开发中“双靶点识别”这一核心挑战，药明康德构建了一个包含逾40亿个双功能分子的专有DEL库。该库中的分子由双功能连接子连接而成，一端衔接靶向E3连接酶或POI的配体，另一端则携带多样化的活性基团（warhead），三者中的任意组分均可负载DNA条形码。这类化合物库可大幅加快PROTAC®候选分子的识别与优化进程，助力项目高效推进。

在双功能化合物库加速配体筛选的同时，连接两个配体的连接子结构也同样至关重要。对于一个有效的PROTAC®分子而言，仅具备对E3连接酶或POI的结合能力远远不够，还必须能促使三元复合物的稳定形成，才能实现目标蛋白的降解。连接子的构型不仅影响复合物的空间构象，还直接关系到分子的溶解度、细胞渗透性及代谢稳定性，其中长度、亲脂性与刚性等理化特性往往决定其成药的潜力。因此，构建多样化的连接子库将有助于提升研发成功率、加快筛选过程。针对这一需求，药明康德的PROTAC®平台已成功合成超过1000种不同类型的连接子，并常备50余种高频使用连接子，助力快速响应筛选与优化需求。

为进一步提升双功能分子的筛选效率，药明康德还配备了双功能一珠一化合物（OBOC）DEL平台。与传统DEL技术将所有化合物混合于溶液中筛选不同，OBOC DEL将每个独特的双功能分子固定在单独的微珠上。在筛选过程中，微珠可与POI和E3连接酶共同孵育，若某个分子能够同时招募两者并在微珠表面形成三元复合物，即可被特异性抗体识别并通过荧光信号及流式细胞仪检测筛出。相比溶液态DEL，OBOC DEL提供了更直接、明确的三元复合物识别能力。此外，命中的双功能分子还可通过光切方式从微珠上释放，可直接进入后续的生化或细胞实验验证流程。

一体化赋能加速PROTAC®药物开发

然而，高通量筛选仅是发现具潜力PROTAC®分子的第一步，项目能否最终成功，还依赖于后续的系统化开发。依托一体化研发平台，药明康德可系统赋能PROTAC®从结构验证到分子机制解析、从DMPK评估到制剂优化全流程开发。公司构建了完善的研究体系，支持验证三元复合物形成及泛素-蛋白酶体通路介导的靶点降解，并搭建了专门应对溶解性、吸收性与代谢稳定性挑战的DMPK研究平台，同时提供多样化制剂方案，提升口服生物利用度。

迄今，药明康德已成功交付超9万个靶向蛋白降解剂分子，覆盖从靶点识别到机制验证等多个环节。依托这一覆盖发现到临床的一体化能力平台，药明康德正加速推动TPD技术转化，为合作伙伴赋能，也为患者带来新的希望。

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."

参考资料：

[1] EMERGING DRUG DISCOVERY STRATEGIES FOR TARGETED PROTEIN DEGRADATION. Retrieved June 3, 2025 from https://wuxibiology.com/wp-content/uploads/2024/01/White-Paper_Targeted-Protein-Degradation.pdf

[2] PROTAC Degraders in Clinical Trails: 2025 Update. Retrieved June 3, 2025 from https://www.biochempeg.com/article/434.html

[3] Targeted Protein Degradation. Retrieved June 10, 2025 from https://wuxibiology.com/solutions/therapeutic-modalities/targeted-protein-degradation-platform-protac/