分子胶：药物发现的新前沿

分子胶通常为分子量低于500 Da的单价小分子，结构简洁，具备良好的药物开发潜力。它们能够通过促进或稳定蛋白–蛋白相互作用，实现对传统“不可成药”靶点的降解，亦或是信号通路的抑制和激活，从而在癌症、糖尿病、心血管疾病及视力障碍等领域打开治疗新局面。沙利度胺（thalidomide）与来那度胺（lenalidomide）便是此类机制在临床中的成功代表。

尽管前景广阔，分子胶的发现仍是一项极具挑战性的科研任务。其功能依赖于在复杂的细胞环境中诱导蛋白间精准的相互作用，而这一过程通常难以预测。即便是轻微的化学修饰，也可能显著改变其活性。因此，若要充分释放分子胶的治疗潜力，必须依赖大规模、系统化的筛选方法与前沿研究策略。

智能化化合物库设计：双重策略拓宽发现空间

在分子胶药物研发的早期阶段，在无偏倚药物筛选时的低命中率始终是一项亟待突破的挑战。为助力合作伙伴有效应对这一难题，药明康德采取了“双轨并进”的策略，构建起一套兼顾广度与深度的化合物库体系：一方面，通过多样化的DNA编码化合物库（DEL）大范围探索新靶点；另一方面，借助聚焦化合物库精细化研究已知蛋白体系，提升发现效率。

在广度探索方面，药明康德构建的多样化DEL库现已汇集超过500亿种结构各异的小分子，每一个化合物都带有独特的DNA条形码，便于快速识别。这些分子骨架多基于已上市药物或临床候选分子，涵盖数千种具有潜在活性的结构母体，构成了一个化学多样性极高、设计精良的化学空间，尤其适用于靶点尚未明确、或缺乏先例的分子胶研究。

在对已知分子胶系统的深入探索中，聚焦化合物库则充分利用现有分子胶结构知识进行靶向设计。例如，针对E3连接酶cereblon（CRBN）的免疫调节药物（IMiDs）化合物库便是典型案例。通过对该蛋白互作区域进行系统性化学修饰，药明康德构建了约600万个精炼化合物，专注于基于CRBN的分子胶发现，有效提升了命中高亲和力、高特异性分子胶的概率，显著增强了对已有构效信息靶点的筛选效率。通过这套双重策略，药明康德不仅拓宽了分子胶药物的发现空间，也为合作伙伴在“未知”与“已知”之间搭建起一座通往临床应用的高效桥梁。

筛选策略：双路径提升命中率

在协助客户推进分子胶药物筛选方面，药明康德针对不同形式的DEL库建立了两套成熟的筛选流程。针对液相DEL，采用下拉实验（pull-down assay），对比单蛋白与双蛋白条件下的化合物富集的差异，以筛选出能促使两种蛋白结合的潜在分子胶；而针对固相载体DEL，则结合荧光标记与细胞分选技术，通过可视化筛选找出可同时结合两种蛋白的微珠，随后进行DNA标签测序，明确化合物结构。这两种筛选路径相辅相成、各展所长，一方面拓宽了筛选维度，另一方面也显著提高了高亲和力配体的命中率，加快了分子胶早期研发节奏。

多维技术集成：突破DEL筛选边界

在分子胶药物的早期发现过程中，药明康德不仅依赖DNA编码化合物库进行筛选，还不断引入并整合多种先进技术，以助力合作伙伴拓展分子胶药物的发现能力。其中，亲和筛选质谱（ASMS）提供无标记筛选手段。药明康德构建了一个涵盖超过37万个小分子的广谱化合物库，通过比较这些分子在单蛋白与双蛋白条件下的质谱信号差异，精准识别出能够促进蛋白–蛋白相互作用的潜在分子胶候选物，从而识别出潜在促互作的小分子。

与此同时，公司还部署高通量筛选（HTS）技术。在“一孔一化合物”的自动化运行模式下，结合蛋白结合能力或降解能力等功能性实验，HTS能迅速锁定具备生物活性的候选分子，大幅提升筛选效率与准确性。通过将ASMS与HTS等多维筛选工具与DEL平台深度融合，药明康德打破了单一筛选方式的限制，让更多不同类型的靶点进入分子胶研究视野，进一步拓宽了分子胶在多类靶点上的研发空间。

依托一体化平台与多维筛选技术，药明康德已构建起覆盖分子胶药物发现全周期的综合解决方案，助力合作伙伴加速从科学突破迈向临床转化。始终秉持“让天下没有难做的药，难治的病”的愿景，这一体系不仅推动科学向临床转化迈进，也为更多患者带来切实可及的新希望。

Bridging the Undruggable: Advancing Molecular Glue Discovery Through Integrated Innovation

Molecular glues represent a transformative approach in drug discovery, offering novel ways to target disease-driving proteins previously considered undruggable. These small molecules induce or stabilize protein–protein interactions (PPIs), enabling degradation or modulation of challenging targets. Yet, identifying effective molecular glues requires navigating complex biological systems and executing systematic, high-precision screening.

To meet this challenge, WuXi AppTec has built a comprehensive molecular glue discovery platform, integrating DNA-Encoded Libraries (DELs), Affinity Selection Mass Spectrometry (ASMS), and High-Throughput Screening (HTS). This toolbox empowers global partners to rapidly translate this modality into real-world therapies.

Molecular Glues: A New Frontier in Drug Discovery

Molecular glues are monovalent small molecules, typically with a molecular weight under 500 Da, and their streamlined structures make them promising drug candidates. They work by promoting or stabilizing protein–protein interactions, which can lead to the degradation of previously “undruggable” targets or modulation of disease-related signaling pathways. This unique mechanism opens the door to new therapeutic possibilities across a range of conditions, including cancer, diabetes, cardiovascular diseases, and vision disorders. Thalidomide and lenalidomide are clinical examples that illustrate the viability of this approach.

However, discovery is inherently difficult due to:

• Unpredictable structure–activity relationships
• Context-dependent PPI requirements
• Low hit rates in unbiased screens

Innovative discovery methods are essential to realize the full therapeutic potential of molecular glues.

Smart Library Design: Dual Strategies for Better Hits

WuXi AppTec addresses early discovery challenges through a dual-pronged DEL strategy:

1. Diversified DELs for Novel Targets

• Over 50 billion structurally diverse molecules
• Built from thousands of bioactive and drug-like scaffolds
• Ideal for targets lacking prior ligands or structure-activity relationship (SAR) information
• DNA barcoding enables rapid identification and deconvolution

2. Focused Libraries for Known Systems

• Tailored using SAR data
• Includes specialized libraries like the IMiD analog collection (~6 million compounds) for CRBN-based glue discovery
• Designed in solution and on-bead formats to optimize screening flexibility and enrich for functional binders

This dual approach maximizes hit diversity while increasing success rates for well-characterized systems.

DEL Screening: Two Validated Approaches

WuXi AppTec applies complementary screening strategies based on DEL format:

• In-solution DEL:

Pull-down assays compare compound enrichment in single- vs. dual-protein conditions to identify candidates that promote PPI formation.

• On-bead DEL:

Fluorescent probes and cell-sorting technology isolate beads binding both proteins. Sequencing then reveals the identities of dual-binders.

Together, these strategies provide orthogonal validation and accelerate lead generation.

Beyond DEL: ASMS and HTS for Expanded Discovery

WuXi AppTec extends its capabilities beyond DEL with:

Affinity Selection Mass Spectrometry 

• Label-free, unbiased screening using a >327,000-compound library
• Measures binding differences between single and dual-protein setups
• Effective for uncovering subtle interaction stabilizers

High-Throughput Screening 

• One-compound-per-well format, paired with functional PPI or degradation assays
• Enables rapid identification of molecular glue candidates based on phenotypic or mechanistic endpoints

These orthogonal methods broaden hit discovery across diverse protein classes and disease contexts.

Integrated Platform for End-to-End Innovation

By uniting cutting-edge screening technologies, tailored library design, and deep scientific expertise, WuXi AppTec offers a fully integrated platform for molecular glue discovery. This approach supports partners across:

• Hit identification and validation
• Mechanistic characterization and degradation profiling
• Lead optimization and SAR development

Aligned with the vision that “every drug can be made and every disease can be treated”, WuXi AppTec is enabling the next generation of therapeutics to reach patients faster, especially in areas where conventional drug modalities have failed.

参考资料：

[1] Molecular Glues Discovery: Challenges and Opportunities. Retrieved July 4, 2025 from https://wuxibiology.com/resource/discovery-of-molecular-glues-challenges-and-opportunities/

免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。