从400亿分子中锁定成药潜力！药明康德一体化平台拓展靶向蛋白降解研发边界

编者按：近年来，新兴疗法持续涌现，重新定义了药物发现的传统边界。作为其中的前沿代表，靶向蛋白降解（TPD）疗法已经成为新药研发的热点。这类可从源头降解致病蛋白的疗法，有望靶向许多长期被认为“不可成药”的靶点。早在TPD技术兴起之初，药明康德就前瞻性地布局了相关能力和技术，搭建了集发现、合成、分析纯化和测试等能力于一体的一体化赋能平台。本文将结合药明康德生物学业务平台团队在美国癌症研究协会（AACR）年会展示的案例，介绍其一体化发现平台如何高效助力TPD潜力分子的发现。

在不久前的2026年美国癌症研究协会（AACR）年会上，靶向蛋白降解（TPD）疗法无疑是备受瞩目的领域之一。其中，从CRBN、VHL等传统E3泛素连接酶向更多新型酶的拓展，成为值得关注的新兴趋势。在这一领域，药明康德生物学平台团队在现场通过壁报展示了两项研究进展。

在其中一项研究中，药明康德生物学平台构建了全新的分子胶库，并筛选鉴定出超过100个苗头化合物，其中包含了不依赖于传统E3连接酶CRBN的分子，为非CRBN类分子胶及新型TPD策略的开发提供了全新路径。

另一项研究则利用DNA编码化合物库（DEL）筛选，探索了新型E3连接酶，并构建了一系列靶向目标蛋白BRD4的蛋白降解靶向嵌合体分子，验证了DEL技术在新型E3连接酶及TPD疗法开发中的作用。

那么，开发新型E3连接酶为何如此关键？这要从TPD类分子的作用机制说起。

一体化发现平台应对TPD挑战

以蛋白降解靶向嵌合体、分子胶为代表的TPD疗法，巧妙地利用了人体内泛素介导的蛋白降解系统，实现对目标蛋白的选择性降解。

这些TPD分子招募的关键酶，正是E3连接酶。在泛素化过程中，E3连接酶负责识别底物蛋白，并将代表着“待降解”的泛素标签贴到目标蛋白上。因此，E3连接酶在很大程度上决定了降解的选择性与效率。

人类编码的E3连接酶数量超过600种，但绝大多数都缺乏已知可用的配体。目前在TPD药物开发中，得到广泛应用的仅有CRBN和VHL等少数几种传统E3连接酶。这不仅限制了化学空间的拓展，也可能导致耐药性风险。

因此，如何系统性地挖掘非传统的E3连接酶并发现相应的小分子配体，成为当前TPD领域亟待突破的方向。

围绕TPD药物发现，药明康德生物学平台构建了覆盖靶点验证、分子发现与功能机制解析的系统化一体化发现平台，能够有效应对异双功能分子、分子胶类等药物在早期研发阶段面临的复杂生物学挑战。

该平台支持TPD领域从活性化合物筛选、评估优化、候选化合物筛选等多阶段的研究。其中，筛选平台整合了DNA编码化合物库、片段筛选、亲和选择质谱（ASMS）及虚拟筛选等多种技术手段，用于高效识别靶蛋白配体与E3连接酶配体，并支持新型连接子设计与复杂双功能分子的优化。

从海量分子中“钓”出潜力配体

以借助DEL筛选新型E3连接酶的壁报为例，研究团队使用筛选平台中的DEL技术，从30个候选E3连接酶出发，对超过400亿化合物的化学空间进行了系统性的亲和力筛选与评估。

在这一过程中，一个名为GID4的候选蛋白脱颖而出。

GID4是CTLH E3泛素连接酶复合物中的底物识别亚基，负责识别、招募需要降解的目标蛋白。已经有研究发现，GID4能够在细胞内靶向异位招募的底物并介导其降解，其作为蛋白降解靶向嵌合体E3连接酶的潜力也得到证实。

通过对超过400亿分子的DEL筛选，研究团队获得了3个系列与GID4有不同亲和力的苗头化合物。但最初的苗头化合物分子量大，并且配体结合率低，限制了其作为结合配体开发TPD分子的能力。

面对挑战，研究团队首先通过对初始苗头化合物系统的截短和片段化，分析结合力测试数据与配体结合率指标，来确定关键药效团的特征。然后基于片段化分子，团队通过配体生长方法设计和分子模拟的方法进一步优化结构，成功发现了分子量低于400、结合力、配体结合效率高的潜力GID4配体分子。

随后，为了验证GID4配体能否开发为TPD分子，团队将其中一个优化的GID4配体和BRD4蛋白配体连接，快速构建了蛋白降解靶向嵌合体，验证了这些TPD分子能够诱导三元复合物的形成，并成功降解目标蛋白BRD4。

完成初步验证后，研究团队需要进一步探索GID4配体，BRD4配体和连接子的最优连接方式。然而蛋白降解靶向嵌合体的优化往往缺少理性设计，在传统药物发现流程中需要花费大量的人力和物力。

在此阶段，药明康德团队的Direct-to-Biology（D2B）平台成为关键引擎，强力驱动靶向蛋白降解药物分子的开发。D2B策略通过在微孔板中进行纳摩尔级的高通量化学反应，直接在微孔板中批量合成化合物并紧接着用于生物测试，在显著减少原料和试剂投入的同时，仅需2-3周时间就可以完成上千个化合物的设计、合成、测试以及初筛结果分析，极大缩短了药物研发周期。

基于该策略，研究团队从内部研发优化的近10个GID4优质配体出发，充分考虑连接子结构多样性，通过组合化学设计系统性探索构效关系（SAR）信息和最优的组合方式。

利用D2B平台，团队在两周内高效完成上百个衍生分子的合成与筛选，获得SAR信息的同时，快速锁定几个以GID4为E3泛素连接酶受体，表现更优的蛋白降解靶向嵌合体分子，其BRD4降解活性较初始苗头化合物提升10倍，为后续开发奠定了坚实基础。

▲D2B策略为SAR研究提供支持，并加速了蛋白降解靶向嵌合体分子的优化进程（图片来源：药明康德生物学平台）

“正如本次AACR会议所呈现的趋势，TPD的研究范围正从依赖少数经典E3连接酶，向着更多元的新型E3连接酶体系拓展，这一转变对药物发现能力提出了更高的要求，”药明康德研发生物学平台负责人、生物学业务平台能力中心负责人苏文姬博士指出，“围绕TPD分子的研发需求，药明康德构建的一体化发现平台整合了多样化的筛选技术，同时提供D2B解决方案，能够在更复杂的化学空间中高效识别并优化新型E3连接酶配体，加速TPD疗法的创新进程。”

TPD崛起：从机制突破到临床加速

过去十年间，TPD疗法迅速崛起，研发管线持续扩展，覆盖癌症、免疫性疾病、神经退行性疾病等多个领域。例如，靶向降解雌激素受体（ER）的蛋白降解靶向嵌合体Veppanu（vepdegestrant）不久前获美国FDA批准上市，为携带ESR1突变的HR+/HER2-乳腺癌患者提供新疗法；新一代分子胶iberdomide同样有望在今年完成FDA审评，用于复发或难治性多发性骨髓瘤。

TPD疗法的广阔前景也吸引了资本的高度关注。就在近期，致力于开发分子胶降解剂的生物技术公司Neomorph宣布完成1亿美元B轮融资，用于推进在研分子胶降解剂NEO-811的1/2期临床试验。

由于结构复杂、分子量较大，这些传统意义上“难以成药”的TPD分子对平台能力提出了更高的要求。

早在2016年，TPD领域的研发刚刚起步，药明康德就前瞻性地布局了相关能力和技术，搭建了集发现、合成、分析纯化和测试等能力于一体的一体化赋能平台。伴随着新型TPD分子的涌现，平台技术的能力已涵盖蛋白降解靶向嵌合体、调节诱导接近靶向嵌合体、分子胶、自噬靶向嵌合体、溶酶体靶向嵌合体、去泛素化酶靶向嵌合体、核糖核酸酶靶向嵌合体、磷酸化诱导嵌合小分子以及抗体偶联降解剂等主要分子类型。

展望未来，随着更多沉睡的E3连接酶被激活，TPD疗法的版图也将进一步扩展，一个更广阔的药物研发空间，正在逐渐显现。

在这段旅途中，药明康德将持续以一体化、端到端的CRDMO赋能平台，助力全球合作伙伴加速TPD等创新疗法的研发生产进程，让科学突破更快为患者带来福祉。

From 40 Billion Molecules to Druggable Potential: WuXi AppTec's Integrated Platform Expands the Boundaries of Targeted Protein Degradation

At the American Association for Cancer Research (AACR) Annual Meeting 2026, targeted protein degradation (TPD) therapies were among the most prominent areas of focus. In particular,the expansion from traditional E3 ligases such as CRBN and VHL to a broader range of novel ligases has emerged as a noteworthy trend.In this field, the WuXi Biology team of WuXi AppTec presented two research updates via posters at the conference.

In one of these studies,WuXi Biology constructed a novel molecular glue library and identified over 100 hit compounds, including CRBN-independent candidates. This work provides a new path for the development of non-CRBN molecular glues and next-generation TPD strategies.

In the other study,the team leveraged DEL screening to explore novel E3 ligases and constructed a series of proteolysis-targeting chimeras targeting the protein BRD4, demonstrating the value of DEL technology in the discovery of novel E3 ligases and the development of TPD therapies.

Why is the development of novel E3 ligases so critical? The answer lies in the mechanism of action of TPD molecules.

An Integrated Discovery Platform to Address TPD Challenges

TPD therapies, represented by proteolysis-targeting chimeras and molecular glues, harness the ubiquitin-mediated protein degradation system within the human body to achieve selective degradation of target proteins.

The key enzymes recruited by these TPD molecules are E3 ligases.In the ubiquitination process, E3 ligases are responsible for recognizing substrate proteins and tagging them with ubiquitin, effectively marking them for degradation. As such,E3 ligases largely determine the selectivity and efficiency of protein degradation.

Humans encode more than 600 E3 ligases, yet the vast majority lack known, tractable ligands. Currently, only a few traditional E3 ligases, such as CRBN and VHL, are widely used in TPD drug development. This not only limits the expansion of chemical space but may also introduce risks of drug resistance.

Therefore,systematically exploring non-traditional E3 ligases and discovering corresponding small-molecule ligands has become a key challenge for the TPD field.

To support TPD drug discovery, WuXi Biology has built a systematic, integrated discovery platform covering target validation, molecule discovery, and functional mechanism characterization. The platform is designed to address the complex biological challenges associated with bifunctional degraders, molecular glues and other therapeutics in early-stage drug discovery.

The platform supports multiple stages of research in the TPD field, including hit finding, hit triage, and candidate selection. Its screening capabilities integrate multiple advanced ligand discovery strategies, including DNA-encoded library (DEL) screening, fragment-based approaches, affinity selection mass spectrometry (ASMS), and virtual screening, enabling efficient identification of both target protein ligands and E3 ligase ligands. In addition, it supports the design and optimization of novel linkers and complex bifunctional molecules.

“Fishing” for Potential Ligands from Vast Chemical Space

Taking the poster on discovering novel E3 ligases via DEL screening as an example,the research team utilized DEL technology within the screening platform to conduct systematic affinity selection and evaluation across a chemical space of more than 40 billion compounds, across 30 candidate E3 ligases.

Through this process, a candidate protein named GID4 stood out.

GID4 is a substrate-recognition subunit of the CTLH E3 ligase complex, responsible for recognizing and recruiting target proteins for degradation. Previous studies have shown that GID4 can mediate the degradation of recruited substrates, highlighting its potential as an E3 ligase component for proteolysis-targeting chimeras.

Through DEL screening of more than 40 billion compounds, the team identified three hit series with varying affinities for GID4.However, the initial hits were characterized by high molecular weight and low ligand efficiency, limiting their potential as ligands for TPD molecule development.

To address these challenges, the team first applied systematic truncation and fragmentation of the initial hits, analyzing binding affinity alongside ligand efficiency metrics to define key pharmacophoric features. Building on these fragments, they then further refined the structures, ultimately identifying a set of promising GID4 ligands with molecular weights below 400 and significantly improved binding affinity and ligand efficiency.

To validate whether these GID4 ligands could be developed into TPD molecules, the team conjugated one optimized GID4 ligand to a BRD4-binding moiety to rapidly construct proteolysis-targeting chimeras. These molecules induced ternary complex formation and successfully degraded the target protein BRD4.

Following the initial validation, further exploration was needed to optimize the combination of GID4 ligands, BRD4 ligands, and linker designs. However, optimization of proteolysis-targeting chimeras often lacks rational design and is resource-intensive in traditional drug discovery workflows.

At this stage, WuXi AppTec’s Direct-to-Biology (D2B) platform became a critical engine that accelerated the development of targeted protein degradation molecules.By enabling nanomole-scale, high-throughput chemical synthesis directly in microplates, followed immediately by biological testing, the D2B approach allows for rapid design, synthesis, testing, and preliminary analysis of thousands of compounds within just 2-3 weeks, while significantly reducing material and reagent consumption.

Leveraging this strategy, the team started with nearly ten internally optimized, high-quality GID4 ligands and systematically explored linker diversity. Through combinatorial chemistry design, they efficiently mapped structure–activity relationships (SAR) and identified optimal combinations of ligands and linkers.

Using the D2B platform, the team synthesized and screened hundreds of derivatives within two weeks, rapidly identifying several GID4-recruiting proteolysis-targeting chimeras with superior degradation activity. These molecules demonstrated a tenfold improvement in BRD4 degradation activity compared with the initial hits, laying a solid foundation for further development.

▲The D2B strategy supports SAR studies and accelerates the optimization of proteolysis-targeting chimera molecules(Image source: WuXi Biology)

“As highlighted at this year’s AACR meeting, the field of TPD is rapidly expanding beyond a handful of classical E3 ligases into a more diverse and complex landscape of novel ligases, raising the bar for drug discovery capabilities,” noted Dr. Wenji Su, Head of Discovery Biology Platform at WuXi AppTec, “WuXi AppTec has established an integrated discovery platform for TPD, bringing together diverse screening technologies with Direct-to-Biology (D2B) solutions. This platform enables the efficient identification and optimization of novel E3 ligase ligands within increasingly complex chemical space, accelerating the innovation of TPD therapeutics.”

The Rise of TPD: From Mechanistic Breakthroughs to Clinical Acceleration

Over the past decade, TPD therapies have risen rapidly, with expanding pipelines spanning oncology, immune diseases, neurodegenerative disorders, and beyond. For example, the proteolysis-targeting chimera Veppanu (vepdegestrant) targeting the estrogen receptor (ER) was recently approved by the U.S. FDA, offering a new treatment option for patients with ESR1-mutant HR+/HER2- breast cancer. Another next-generation molecular glue, iberdomide, is also expected to complete FDA review this year for relapsed or refractory multiple myeloma.

The strong promise of TPD therapies has also attracted significant investor interest. Recently, Neomorph announced the completion of a $100 million Series B financing round to advance its molecular glue degrader NEO-811 into Phase 1/2 clinical trials.

Due to their structural complexity and relatively large molecular weight, these traditionally “undruggable” TPD molecules place higher demands on platform capabilities.

As early as 2016, when TPD research was still in its early stage, WuXi AppTec had already made forward-looking investments in this field, establishing an integrated enabling platform that combines discovery, synthesis, analytical purification, and testing capabilities. With the emergence of new TPD modalities, the platform now supports a broad range of molecular types, including proteolysis-targeting chimeras, regulated induced proximity targeting chimeras, molecular glues, autophagy-targeting chimeras (AUTACs), lysosome-targeting chimeras (LYTACs), deubiquitinase-targeting chimeras (DUBTACs), ribonuclease-targeting chimeras (RIBOTACs), phosphorylation-inducing chimeric small molecules (PHICS), and degrader-antibody conjugates (DAC).

Looking ahead, as more previously untapped E3 ligases are unlocked, the landscape of TPD therapies will continue to expand, revealing an increasingly vast space for drug discovery.

Throughout this journey, WuXi AppTec will continue to enable global customers with its integrated, end-to-end CRDMO platform, accelerating the development and manufacturing of innovative therapies such as TPD, and helping customers accelerate drug development for patients worldwide.

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