靶向蛋白降解（TPD）療法正憑借獨特的作用機制，叩開“不可成藥”靶點的大門。然而，這類新型分子的復雜結構也面臨著現實的研發瓶頸。其中一項挑戰在于：由于分子量大、極性強，TPD分子在穿越細胞膜時頻頻受阻。

分子設計得再精巧，若無法進入細胞，療效便無從談起。

在研發一款TPD分子時，一家公司因候選分子透膜性不足，導致降解效果遠低于預期，項目一度陷入僵局。為提高分子透膜性能，他們尋求藥明康德協助。

藥明康德生物學平臺（WuXi Biology）團隊接手后，通過系統分析分子結構與靶點信息，迅速明確了分子設計優化方向；接下來，如何高效篩選目標分子成為新的關鍵挑戰。

TPD分子的早期發現離不開對大量化合物的快速評估。在傳統流程中，分子需經歷設計合成、分離純化，再進入生物檢測體系，整個過程周期冗長。為突破這一瓶頸，團隊啟用了搭載D2B（Direct-to-Biology）能力的一體化篩選平臺，使高通量篩選得到的化合物無需“繞路”，即可直接進入生物檢測流程。

僅一個月內，團隊就完成了約2000個分子的設計、合成與檢測。通過快速迭代篩選，項目團隊提出了新的化合物設計思路，改善了分子的透膜性能，推動項目回到前進軌道。

為這一過程按下加速鍵的，正是藥明康德生物學平臺的新一代高通量篩選平臺：HTS 2.0。

▲藥明康德生物學平臺HTS 2.0能力示意圖（圖片來源：藥明康德生物學平臺）

HTS“升級”，拓展化學空間

自誕生以來，高通量篩選（HTS）技術已經成為早期藥物發現的核心技術。HTS改變了傳統低效的手工篩選模式，顯著提升了篩選速度與規模。藥明康德的HTS篩選平臺早年就已經將自動化系統引入該領域，集成了多種移液工作站，孵育平臺以及實驗檢測手段，在1536微孔板上實現了多線程，全天候的自動化藥物篩選，在提升篩選通量的同時，提供高質量的篩選數據，讓大規模、系統性的苗頭化合物篩選成為現實。

早在2010年前，藥明康德生物學平臺便已布局HTS技術能力。十余年來，該平臺支持了數百個苗頭化合物的發現，覆蓋了蛋白酶、G蛋白偶聯受體（GPCR）、分子膠、轉錄因子等多種靶點與分子類型。

近年來，隨著治療靶點與分子類型不斷拓展，越來越復雜的作用機制對篩選體系提出更高要求。正是在這一背景下，藥明康德生物學平臺推出了升級版HTS 2.0。

在藥物篩選中，高質量的化合物庫是苗頭化合物發現的起點。如同一座等待被探索的“化學礦山”，化合物庫的規模與多樣性直接影響發現成功的概率。

HTS 2.0平臺升級后，化合物庫已拓展至37萬種小分子，新增約10萬種。升級的價值不僅是簡單的數量增長，化合物骨架數量也提升了21%，顯著增加了化合物分子的多樣性。這意味著平臺能夠覆蓋更廣闊的化學空間，讓研究人員在項目早期更有機會發現目標分子。

在標準化合物庫之外，HTS 2.0平臺還支持圍繞特定靶點構建定制化合物庫。這一能力在面對“難以成藥”靶點時尤為關鍵。在一項合作項目中，由于市售通用化合物庫難以滿足特殊靶點需求，藥明康德生物學平臺在兩個月內完成了超過20萬種化合物的設計、合成與篩選，顯著提升了苗頭化合物的發現概率。

從擴展化學空間，到圍繞靶點快速構建專屬分子庫，HTS 2.0平臺正在延伸早期藥物發現的探索邊界。

HTS 2.0如何重構早期篩選

擁有豐富的化合物庫，邁出了藥物發現的第一步。能否從海量分子中快速識別出有效且可優化的結構，還取決于篩選體系的能力邊界。

HTS 2.0并非單一的技術平臺，而是將生物化學篩選、細胞篩選、親和質譜篩選以及高內涵篩選整合于同一套分子發現體系中：

• 生物化學篩選（Biochemical assay）直接檢測化合物與體外重組蛋白靶點的結合或活性調控，常用于激酶、蛋白酶等靶點的篩選，具有成本低，通量極高的特點；

• 基于細胞的功能篩選（Cell-based assay）在活細胞環境中檢測化合物對靶點相關功能的調節（如第二信使、報告基因），能反映化合物的膜通透性和相對生理條件下的活性；

• 親和質譜篩選（ASMS）通過將化合物池（200~400個化合物混合在一個微孔內）與靶蛋白孵育，利用質譜檢測蛋白結合分子，其核心優勢是無需標記蛋白，并通過使用化合物池進一步提高篩選通量、降低篩選成本；

• 高內涵篩選（High-content screen）基于自動化顯微成像和圖像分析，在細胞水平多參數檢測化合物對細胞形態、蛋白定位、細胞器等的影響，是一種最主要的表型篩選手段。

四種篩選能力既是不同篩選策略的入口，也可組成互補和遞進的鏈條。HTS 2.0平臺致力于將不同篩選能力協同作用，為每一個客戶的篩選項目提供定制化的開發策略，構成了一條獨特的從海量分子庫到苗頭化合物的發現路徑。

D2B重新編寫合成-生物測試路徑

發現苗頭化合物之后，傳統的優化流程通常需經歷多輪“設計-合成-測試”的迭代，每一輪周期往往以月計算。這一過程不僅漫長，耗資不菲，更充滿了不確定性。比如TPD分子的優化往往缺少理性設計，在傳統藥物結構優化流程中需要花費大量的人力和物力。

面對這一挑戰，HTS 2.0平臺搭載的D2B能力成為關鍵引擎。D2B策略通過在微孔板中進行納摩爾級的高通量化學反應，跳過復雜的純化步驟，直接在微孔板中批量合成化合物并緊接著用于生物測試，由此，“設計-合成-測試”流程不再是割裂的多個階段，而是被整合為連續循環，打通了化合物合成與生物學測試之間的壁壘。

在HTS 2.0平臺，憑借數萬種分子砌塊儲備以及數十種化學反應的開發，D2B策略能夠在三周內完成超過3000個新TPD化合物的合成和檢測，幫助研究人員更快識別有效結構，并迅速確定先導化合物的優化方向。

自正式推出以來，結合了D2B能力的HTS 2.0平臺已經助力多種TPD分子的篩選與優化，加速了包括分子膠在內的結構優化進程。

不同于傳統小分子，分子膠通常不依賴明確的結合口袋，其作用機制復雜，缺乏成熟的理性設計路徑。

面對這一挑戰，團隊在利用常規小分子化合物庫的同時，還設計了分子膠化合物庫。通過一體化篩選與D2B的聯用，HTS 2.0平臺能快速完成海量化合物的篩選與測試，助力挖掘苗頭化合物，緊接著在2-3周完成“設計-合成-測試”流程，加速將苗頭化合物發現推進至先導化合物優化階段。

目前，藥明康德生物學平臺團隊已利用D2B方案賦能多個分子膠藥物的開發。

如今，HTS 2.0平臺正幫助客戶將早期藥物發現中那些高度不確定的環節，變得更具可預期性、更高效。當化合物庫覆蓋更廣闊的化學空間，當合成與生物測試之間的壁壘被打通，藥物發現的早期階段有了一條清晰可循的加速路徑。

這正是藥明康德“讓天下沒有難做的藥，難治的病”這一愿景的生動實踐。讓“難以成藥”靶點有機會被識別與攻克，讓復雜分子找到高效的優化路徑，藥明康德正通過一體化賦能平臺，助力全球生物醫藥創新者探索更高效的新藥研發路徑，讓更多創新療法惠及患者。

▲欲了解WuXi Biology如何賦能藥物研發，請長按掃描上方二維碼，與藥明康德生物學業務平臺聯系

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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