同行致远 | “让不可能成为现实”！一体化平台如何加速创新PROTAC®分子开发 | Bilingual

编者按：蛋白降解靶向嵌合体（PROTAC®）可选择性降解与疾病相关的蛋白，已成为新药开发的热点领域之一，尤其有望靶向那些曾被视为“不可成药”的靶点。然而，PROTAC®分子量大、结构复杂，这在药物开发过程中对其合成和放大造成巨大挑战。当某医药公司在推进一款有前景的PROTAC®类候选药物进入临床前评估阶段时，面临一项艰巨任务：需通过复杂的27步合成工艺快速放大生产一款PROTAC®分子。药明康德研发化学服务部（RCS）团队迎难而上，凭借多年的经验积累、多样化的合成策略以及跨职能协作，仅用29天便交付出足量的高纯度化合物，助力客户顺利完成关键测试，按节点推进研发进程。

PROTAC®类药物开发的挑战

通过选择性降解致病蛋白，PROTAC®类药物正逐步改变传统药物发现的范式。这类分子虽被归类为小分子药物，但由于其分子量大、结构复杂，往往不符合传统“成药性”标准，给化学合成、规模放大及后续开发带来了诸多挑战。因此，推进PROTAC®类候选药物通常需要进行大量的结构-活性关系迭代研究，合成并筛选各种反应条件。

在本项目中，客户的主打化合物虽已完成初步筛选，但要顺利推进至下一阶段开发，仍面临重大挑战：该化合物的合成路线长达27步，目前仅在克级规模完成验证。客户希望在30天内完成百克级的放大生产，用于关键的临床前测试，这对时间和资源提出了极高要求。根据行业经验法则，“每次放大不超过十倍”是确保工艺可控的基本原则，这意味着必须在极短时间内并行完成2至3轮放大验证。

进一步增加项目复杂性的是，该化合物具有较强极性、分子尺寸较大，且纯化流程繁复，这对合成放大过程中的质量控制与批次间一致性带来了更大挑战。在如此紧迫的时间窗口内，任何原料采购、反应实施或纯化步骤的延误都可能影响整体进度，加剧项目执行难度。

迅速响应，流程高效协同

为应对这一挑战，药明康德RCS团队制定了全面的跨团队响应方案。依托涵盖合成、分析与纯化的一体化化学平台，团队绘制了详细的执行计划，将原本需数月完成的任务压缩至不到五周。

共有40名化学家组成五个协同小组，通过无缝衔接的方式同步开展工艺优化与放大工作。其中一个关键中间体合成涉及六步合成反应，需耗时21天，成为30天紧迫期限中的瓶颈。为克服这一难题，RCS团队通过并行开展其他关键反应，最大程度缩短等待时间，确保中间体持续生产不中断。

▲在29天内成功交付181克目标PROTAC®化合物（图片来源：参考资料[1]）

这一高效协同得益于药明康德具备支持复杂合成的技术平台。例如，流动化学平台可在具挑战性的条件下提高反应安全性与效率；高通量筛选平台并行测试多种反应条件，通常可在两个工作日内获得结果；光氧化还原化学平台则在温和条件下扩展了多官能团分子的合成灵活性。这些整合、可扩展的平台能力助力快速推进并高效执行整个合成流程。

与此同时，采购与物流团队确保起始原料及时到位，分析团队则优化分离与纯化工艺，进一步缩短交付周期。整个项目期间与客户保持透明持续沟通，实现实时决策、灵活应对，并在每一开发阶段保持高度协同。

让“不可能”成为现实

凭借严密的计划与高效执行，药明康德在29天内成功交付181克目标化合物，满足了客户用于下游测试的关键时间要求。此外，产品的质量与一致性完全符合客户所有规格要求，使合作伙伴得以按计划启动临床前评估。“药明康德团队让不可能成为现实。”客户表示。

本项目不仅实现了重要的交付里程碑，该项目还展示了药明康德RCS团队如何有效支持合作伙伴推进PROTAC®等复杂药物模式的开发。迄今为止，药明康德已成功合成超过数万个PROTAC®分子，包括1000多种连接子和60个系列的靶蛋白配体，凭借这一深厚经验，团队协同客户优化发现流程、加速开发进度。这种合作模式证明，选择合适的合作伙伴能有效加速推动科学的创新转化。

随着药物开发人员日益关注靶向蛋白降解领域，力求攻克此前无法成药的靶点，药明康德将继续成为推动这些突破的可靠合作伙伴。秉持“让天下没有难做的药，难治的病”的愿景，我们致力于为全球合作伙伴提供快速、灵活、高效、可靠的小分子新药研发一站式解决方案，以更快速高效地将突破性疗法带给患者。

Making the Impossible Possible: Accelerated PROTAC®Synthesis in 29 Days

Proteolysis-targeting chimeras (PROTAC®s), which induce the selective degradation of disease-related proteins, have emerged as a promising therapeutic modality—especially for targeting proteins once considered undruggable. However, their high molecular weight and structural complexity present significant challenges for synthesis and scale-up during drug development. When a global pharmaceutical company set out to advance a promising PROTAC® candidate into preclinical evaluation, it faced a particularly difficult task: rapidly scaling up a highly polar molecule through a demanding 27-step synthesis route. WuXi AppTec’s Research Chemistry Services (RCS) team rose to the challenge, applying deep scientific expertise, various synthesis strategies, and cross-functional coordination to deliver 181 grams of high-purity compound in just 29 days—enabling the client to meet an aggressive testing schedule and stay on track for key development milestones.

Challenges of PROTAC®Development

PROTAC®s are reshaping drug discovery by enabling the selective degradation of disease-causing proteins. However, although categorized as small molecules, their high molecular weight and structural complexity often lead to reduced drug-like properties. These characteristics pose significant challenges for chemical synthesis, scale-up, and overall developability. As a result, advancing PROTAC® candidates typically involves iterative and resource-intensive structure–activity relationship studies, requiring the synthesis and screening of different reaction conditions.

For this project, the client’s lead compound had already been identified—but progressing it to the next phase of development posed an immediate challenge. The existing 27-step synthesis route had only been proven at gram scale. Scaling this up to over 100 grams within a month—while ensuring product quality and reproducibility—was a challenging task, especially given the compound’s polarity, size, and the complexity of purification.

The timeline added further pressure. The client needed material for critical testing in exactly 30 days. The typical rule-of-thumb for chemical scale-up—no more than a tenfold increase per iteration—meant that multiple validation rounds were required in parallel. Any delays in procurement, synthesis, or purification could derail the entire timeline.

A Rapid Response and Streamlined Operations in Action

To address the challenge, WuXi AppTec’s RCS team developed a comprehensive cross-functional response plan.Leveraging its integrated chemistry platform—spanning synthesis, analysis, and purification—the team created a detailed execution roadmap to compress what would normally take months into less than five weeks.

A total of 40 chemists, organized into five collaborative teams, were mobilized to carry out parallel process optimization and scale-up through seamless coordination. One of the initial intermediates requiring six synthesis steps and taking 21 days to complete posed a significant bottleneck within the tight 30-day deadline. To overcome this,the RCS team strategically minimized idle time by running other critical reactions in parallel, ensuring that intermediate materials were continuously in production.

▲Delivering 181 grams of compound in 29 days (Source: Ref.[1])

This efficient coordination was made possible by WuXi AppTec’s suite of enabling technology platforms designed to support complex synthesis like PROTAC®s. The flow chemistry platform enhanced safety and efficiency under challenging conditions, while the high-throughput screening platform accelerated reaction optimization by testing multiple conditions in parallel—often delivering results within two working days. The photoredox chemistry platform, operating under mild conditions, further expanded synthetic flexibility for complex, multifunctional molecules. Together, these integrated and scalable capabilities enabled rapid progress and seamless execution across the synthesis workflow.

At the same time, procurement and logistics teams ensured timely access to starting materials, while analytical scientists refined separation and purification processes to further reduce turnaround time. Transparent and continuous communication with the client throughout the project allowed for real-time decision-making, flexibility, and full alignment at every stage of development.

Turned the Impossible into Reality

Thanks to seamless planning and execution,WuXi AppTec delivered 181 grams of the target compound in just 29 days—within the critical timeline for downstream testing.The quality and consistency of the material met all customer specifications, enabling the partner to initiate preclinical evaluations as planned. “The WuXi AppTec team turned the impossible into reality,” the client shared.

Beyond this milestone, the project is an example of how WuXi AppTec’s integrated RCS team can effectively support partners in advancing complex drug modalities like PROTAC®s.Drawing on its extensive experience—having synthesized tens of thousands of PROTAC®molecules, including more than 1,000 linkers and 60 series of target protein ligands—WuXi AppTec worked closely with the pharmaceutical company to streamline discovery and accelerate development.This collaboration demonstrates how the right partnership can help translate scientific innovation into real therapeutic potential.

As drug developers increasingly turn to targeted protein degradation to address previously undruggable targets, WuXi AppTec remains a dedicated partner in advancing these breakthroughs. Guided by our vision that "every drug can be made and every disease can be treated," we provide scalable solutions, deep scientific expertise, and seamless collaboration to help partners bring transformative therapies to patients more quickly and efficiently.

参考资料：

[1] How to Accelerate the Synthesis of PROTACs: Strategies and Case Studies. Retrieved July 9, 2025 from https://wuxibiology.com/resource/how-to-accelerate-the-synthesis-of-protacs-strategies-and-case-studies/

[2] 研发化学服务部. Retrieved July 14, 2025 from https://rcs.wuxiapptec.com.cn/

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