“救回”陷入僵局的分子！药明康德筛选平台升级，按下分子发现加速键 | Bilingual

靶向蛋白降解（TPD）疗法正凭借独特的作用机制，叩开“不可成药”靶点的大门。然而，这类新型分子的复杂结构也面临着现实的研发瓶颈。其中一项挑战在于：由于分子量大、极性强，TPD分子在穿越细胞膜时频频受阻。

分子设计得再精巧，若无法进入细胞，疗效便无从谈起。

在研发一款TPD分子时，一家公司因候选分子透膜性不足，导致降解效果远低于预期，项目一度陷入僵局。为提高分子透膜性能，他们寻求药明康德协助。

药明康德生物学平台（WuXi Biology）团队接手后，通过系统分析分子结构与靶点信息，迅速明确了分子设计优化方向；接下来，如何高效筛选目标分子成为新的关键挑战。

TPD分子的早期发现离不开对大量化合物的快速评估。在传统流程中，分子需经历设计合成、分离纯化，再进入生物检测体系，整个过程周期冗长。为突破这一瓶颈，团队启用了搭载D2B（Direct-to-Biology）能力的一体化筛选平台，使高通量筛选得到的化合物无需“绕路”，即可直接进入生物检测流程。

仅一个月内，团队就完成了约2000个分子的设计、合成与检测。通过快速迭代筛选，项目团队提出了新的化合物设计思路，改善了分子的透膜性能，推动项目回到前进轨道。

为这一过程按下加速键的，正是药明康德生物学平台的新一代高通量筛选平台：HTS 2.0。

▲药明康德生物学平台HTS 2.0能力示意图（图片来源：药明康德生物学平台）

HTS“升级”，拓展化学空间

自诞生以来，高通量筛选（HTS）技术已经成为早期药物发现的核心技术。HTS改变了传统低效的手工筛选模式，显著提升了筛选速度与规模。药明康德的HTS筛选平台早年就已经将自动化系统引入该领域，集成了多种移液工作站，孵育平台以及实验检测手段，在1536微孔板上实现了多线程，全天候的自动化药物筛选，在提升筛选通量的同时，提供高质量的筛选数据，让大规模、系统性的苗头化合物筛选成为现实。

早在2010年前，药明康德生物学平台便已布局HTS技术能力。十余年来，该平台支持了数百个苗头化合物的发现，覆盖了蛋白酶、G蛋白偶联受体（GPCR）、分子胶、转录因子等多种靶点与分子类型。

近年来，随着治疗靶点与分子类型不断拓展，越来越复杂的作用机制对筛选体系提出更高要求。正是在这一背景下，药明康德生物学平台推出了升级版HTS 2.0。

在药物筛选中，高质量的化合物库是苗头化合物发现的起点。如同一座等待被探索的“化学矿山”，化合物库的规模与多样性直接影响发现成功的概率。

HTS 2.0平台升级后，化合物库已拓展至37万种小分子，新增约10万种。升级的价值不仅是简单的数量增长，化合物骨架数量也提升了21%，显著增加了化合物分子的多样性。这意味着平台能够覆盖更广阔的化学空间，让研究人员在项目早期更有机会发现目标分子。

在标准化合物库之外，HTS 2.0平台还支持围绕特定靶点构建定制化合物库。这一能力在面对“难以成药”靶点时尤为关键。在一项合作项目中，由于市售通用化合物库难以满足特殊靶点需求，药明康德生物学平台在两个月内完成了超过20万种化合物的设计、合成与筛选，显著提升了苗头化合物的发现概率。

从扩展化学空间，到围绕靶点快速构建专属分子库，HTS 2.0平台正在延伸早期药物发现的探索边界。

HTS 2.0如何重构早期筛选

拥有丰富的化合物库，迈出了药物发现的第一步。能否从海量分子中快速识别出有效且可优化的结构，还取决于筛选体系的能力边界。

HTS 2.0并非单一的技术平台，而是将生物化学筛选、细胞筛选、亲和质谱筛选以及高内涵筛选整合于同一套分子发现体系中：

• 生物化学筛选（Biochemical assay）直接检测化合物与体外重组蛋白靶点的结合或活性调控，常用于激酶、蛋白酶等靶点的筛选，具有成本低，通量极高的特点；

• 基于细胞的功能筛选（Cell-based assay）在活细胞环境中检测化合物对靶点相关功能的调节（如第二信使、报告基因），能反映化合物的膜通透性和相对生理条件下的活性；

• 亲和质谱筛选（ASMS）通过将化合物池（200~400个化合物混合在一个微孔内）与靶蛋白孵育，利用质谱检测蛋白结合分子，其核心优势是无需标记蛋白，并通过使用化合物池进一步提高筛选通量、降低筛选成本；

• 高内涵筛选（High-content screen）基于自动化显微成像和图像分析，在细胞水平多参数检测化合物对细胞形态、蛋白定位、细胞器等的影响，是一种最主要的表型筛选手段。

四种筛选能力既是不同筛选策略的入口，也可组成互补和递进的链条。HTS 2.0平台致力于将不同筛选能力协同作用，为每一个客户的筛选项目提供定制化的开发策略，构成了一条独特的从海量分子库到苗头化合物的发现路径。

D2B重新编写合成-生物测试路径

发现苗头化合物之后，传统的优化流程通常需经历多轮“设计-合成-测试”的迭代，每一轮周期往往以月计算。这一过程不仅漫长，耗资不菲，更充满了不确定性。比如TPD分子的优化往往缺少理性设计，在传统药物结构优化流程中需要花费大量的人力和物力。

面对这一挑战，HTS 2.0平台搭载的D2B能力成为关键引擎。D2B策略通过在微孔板中进行纳摩尔级的高通量化学反应，跳过复杂的纯化步骤，直接在微孔板中批量合成化合物并紧接着用于生物测试，由此，“设计-合成-测试”流程不再是割裂的多个阶段，而是被整合为连续循环，打通了化合物合成与生物学测试之间的壁垒。

在HTS 2.0平台，凭借数万种分子砌块储备以及数十种化学反应的开发，D2B策略能够在三周内完成超过3000个新TPD化合物的合成和检测，帮助研究人员更快识别有效结构，并迅速确定先导化合物的优化方向。

自正式推出以来，结合了D2B能力的HTS 2.0平台已经助力多种TPD分子的筛选与优化，加速了包括分子胶在内的结构优化进程。

不同于传统小分子，分子胶通常不依赖明确的结合口袋，其作用机制复杂，缺乏成熟的理性设计路径。

面对这一挑战，团队在利用常规小分子化合物库的同时，还设计了分子胶化合物库。通过一体化筛选与D2B的联用，HTS 2.0平台能快速完成海量化合物的筛选与测试，助力挖掘苗头化合物，紧接着在2-3周完成“设计-合成-测试”流程，加速将苗头化合物发现推进至先导化合物优化阶段。

目前，药明康德生物学平台团队已利用D2B方案赋能多个分子胶药物的开发。

如今，HTS 2.0平台正帮助客户将早期药物发现中那些高度不确定的环节，变得更具可预期性、更高效。当化合物库覆盖更广阔的化学空间，当合成与生物测试之间的壁垒被打通，药物发现的早期阶段有了一条清晰可循的加速路径。

这正是药明康德“让天下没有难做的药，难治的病”这一愿景的生动实践。让“难以成药”靶点有机会被识别与攻克，让复杂分子找到高效的优化路径，药明康德正通过一体化赋能平台，助力全球生物医药创新者探索更高效的新药研发路径，让更多创新疗法惠及患者。

▲欲了解WuXi Biology如何赋能药物研发，请长按扫描上方二维码，与药明康德生物学业务平台联系

How WuXi AppTec’s Upgraded Screening Platform Accelerates Molecular Discovery

Targeted protein degradation (TPD) therapies are opening new possibilities for previously challenging drug targets through distinct mechanisms of action. However, the structural complexity of these novel molecules also introduces practical development challenges. One key issue is that their ability to cross cell membranes is restricted by high molecular weight and strong polarity.

Even with sophisticated molecular design, insufficient cellular permeability may limit therapeutic potential.

During the development of a TPD candidate, one company experienced this exact problem: insufficient membrane permeability of the candidate led to degradation activity far below expectations and the project stalled. To improve membrane permeability, they sought assistance from WuXi AppTec.

After taking on the program, the WuXi Biology team at WuXi AppTec conducted a systematic analysis of molecular structures and target information and rapidly defined directions for molecular design optimization. The next critical challenge was how to efficiently screen target molecules.

Early discovery of TPD molecules relies on rapid evaluation of large numbers of compounds. In traditional workflows, compounds typically undergo design, synthesis, isolation, and purification before entering biological testing systems, resulting in lengthy development cycles.

To address this bottleneck, the team applied its integrated screening platform equipped with Direct-to-Biology (D2B) capabilities. In this system, compounds generated through high-throughput synthesis can proceed directly into biological testing workflows without intermediate isolation steps.

Within a single month, the team completed the design, synthesis, and testing of approximately 2,000 molecules. Through rapid iterative screening, the team identified new compound design strategies that improved membrane permeability and helped move the project forward.

Supporting this acceleration was HTS 2.0, a next-generation high-throughput screening platform developed by WuXi Biology.

Expanding Chemical Space Through HTS 2.0

Since its emergence, high-throughput screening (HTS) has become a cornerstone in early drug discovery. HTS transformed inefficient manual screening approaches and enabled large-scale, systematic identification of hits. WuXi AppTec’s HTS platform adopted automation systems early on, which has integrated multiple liquid-handling workstations, incubation platforms, and detection modalities to run multi-threaded, around-the-clock automated screening on 1536-well plates. This approach increases throughput while delivering high quality screening data, enabling large-scale, systematic hit discovery.

WuXi Biology established its HTS capabilities before 2010. Over the past decade, the platform has supported the discovery of hundreds of hits across multiple targets and molecular categories, including enzymes, G protein-coupled receptors (GPCRs), and molecular glues.

In recent years, the continued expansion of therapeutic targets and molecular modalities has placed increasing demands on screening systems. HTS 2.0 was developed in response to the evolving needs.

A high-quality compound library serves as the starting point for hit discovery. Its scale and diversity directly influence the probability of identifying promising molecules.

The upgraded HTS 2.0 platform includes a compound library containing 370,000 small molecules, representing an increase of approximately 100,000 compounds compared with the previous platform. The upgrade extends beyond numerical growth alone: the number of molecular scaffolds has increased by 21%, enabling broader coverage of chemical space and increasing the likelihood of identifying target molecules during early-stage discovery.

Beyond the standard compound libraries, HTS 2.0 also supports the construction of customized libraries tailored to specific targets. This capability is particularly important for challenging targets. In one collaborative project, commercially available general libraries could not adequately address the target requirements. The WuXi Biology team designed, synthesized, and screened over 200,000 compounds within two months, significantly improving the probability of hit discovery.

From expanding chemical space to rapidly constructing target-specific libraries, HTS 2.0 continues to extend the boundaries of early drug discovery.

How HTS 2.0 Enhances Early-Stage Screening

Building a diverse compound library is the first step in drug discovery. The ability to rapidly identify active and optimizable structures from a vast pool of molecules also depends on the capabilities of screening system.

HTS 2.0 is not a single technology platform. Instead, it integrates biochemical assays, cell-based assays, affinity selection mass spectrometry (ASMS), and high-content screening (HCS) into a unified molecular discovery system.

• Biochemical assays directly detect compound binding or activity modulation against in vitro recombinant protein targets, commonly used for kinases, proteases, and similar targets. They offer low cost and very high throughput.

• Cell-based assays measure compound modulation of target related functions in live cells (e.g., second messengers, reporter genes), reflecting membrane permeability and activity under more physiological conditions.

• ASMS incubates pools of compounds (200-400 compounds per well) with the target protein and uses mass spectrometry to detect binders. Its major advantages are label-free detection, increased throughput through pooled screening, and reduced cost.

• High-content screening (HCS) combines automated microscopy and image analysis to measure multi-parametric cellular responses, including morphology, protein localization, and organelle status, making it a primary phenotypic screening approach.

These four screening capabilities serve both as distinct entry points and as complementary, progressive steps. HTS 2.0 orchestrates their synergy and provides bespoke development strategies for each client project, forming a unique discovery pathway from vast compound libraries to hits.

D2B: Bridging Synthesis and Biological Testing

After hit identification, conventional optimization typically involves multiple “design-synthesis-test” iterations, each often taking months. This process is time consuming, costly, and uncertain. TPD optimization, for example, frequently lacks rational design principles and demands extensive resources.

The D2B capability embedded in HTS 2.0 is a key engine driving drug development. D2B performs nanomolar-scale high-throughput chemistry directly in microplates, skipping complex purification steps and immediately using the crude reaction mixtures in biological assays. Thus, the “design-synthesis-test” cycle becomes an integrated, continuous loop that breaks down the barrier between synthesis and biological evaluation.

Leveraging a repository of tens of thousands of building blocks and dozens of developed reaction types, the D2B strategy on HTS 2.0 can synthesize and test over 3,000 new TPD compounds within three weeks, helping researchers rapidly identify active chemotypes and define lead optimization directions.

Since its launch, the HTS 2.0 platform combined with D2B capabilities has supported the screening and optimization of multiple complex molecular modalities. A typical application is the rational design of molecular glues.

Unlike traditional small molecules, molecular glues generally do not rely on defined binding pockets; their mechanisms are complex and lack mature rational design routes.

To tackle this, the team created dedicated molecular glue libraries alongside conventional small molecule collections. By combining integrated screening and D2B, HTS 2.0 can rapidly screen and test huge numbers of compounds, identify hits, and then complete a “design-synthesis-test” cycle within two to three weeks, accelerating progression from hit discovery to lead optimization.

To date, WuXi Biology has applied D2B solutions to enable the development of multiple molecular glue programs.

Today, the HTS 2.0 platform is helping customers improve efficiency and decision-making during early-stage drug discovery. As compound libraries expand into broader chemical space and barriers between synthesis and biological testing are reduced, early-stage drug discovery gains a clearer and more efficient development pathway.

This reflects WuXi AppTec's vision: "Every drug can be made, and every disease can be treated." Through its integrated enabling platform, WuXi AppTec continues to support global biopharmaceutical innovators in exploring more efficient approaches, and bringing new therapies to patients worldwide.

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