这个项目“不好做”，药明康德如何用13个月交出560个分子？

在科学探索的旅程中，最激动人心的时刻，也许不是抵达终点的瞬间，而是在未知迷雾中坚定前行的过程。新药研发，正是这样一场充满不确定性的探索。当一个前所未见的分子结构出现时，它带来的既是突破的希望，也是重重难关。而将希望转化为现实的，从来不只是灵光一现的发现，更是漫长跋涉中一次次跨越障碍的坚持与智慧。

多年前，一位客户带着一款“特别的”苗头活性分子，与药明康德研发化学服务部（Research Chemistry Services，RCS）建立合作。这个分子量很大、结构奇特的研究项目，正是后来发展为行业热门研发方向的蛋白降解靶向嵌合体（PROTAC）类型。不同于传统小分子抑制剂，这类分子不直接抑制蛋白活性，而是借助细胞内的泛素-蛋白酶体系统，将致病蛋白精准标记并清除。这种独特的作用机制，使其有望攻克传统意义上“不可成药”的靶点；但与此同时，其高分子量、复杂化学结构以及特殊的理化性质，也为合成与开发带来了前所未有的挑战。

彼时，整个靶向蛋白降解（TPD）领域都尚处发展早期，尤其从事于PROTAC领域探索的企业和机构为数不多，行业既缺少成熟的技术先例，也还没有产品真正打通从研发到商业化生产的完整路径。这显然是一条布满风险与未知的道路。项目启动之初，客户坦诚地说：“这个项目不好做。”

一场攻坚：13个月，560个分子

面对诸多难以提前预知的各类挑战，药明康德RCS团队没有退缩，而是选择迎难而上。

经过系统评估，团队很快锁定这款分子的两大核心挑战——分子合成与分离纯化，并开始探索解决方案。

在分子合成方面，客户最初提供的合成路线收率不高、步骤繁琐，且无法支撑后续放大生产。而针对这类全新分子类型，可借鉴的常规反应非常有限，团队几乎需要从“零”开始探索。RCS团队反复实验、持续尝试，并引入电化学、光化学、流动化学等多个化学技术平台，最终开发出一条更简洁高效的工艺路线，显著提升了收率。这条路线也成功用于后续放大生产，为项目的高效推进奠定了坚实基础。

在分离纯化方面，该分子溶解性极差，且对碱不稳定，导致传统分离条件下的回收率极低。团队通过自主摸索，创新性地采用“边分离边用酸快速中和”的策略，及时稳定目标分子。这一方法学上的调整看似微小，却极大助力实现了高纯度分离与理想回收率的双重提升。

凭借合成与纯化两端的突破，团队交出了一份超出客户预期的答卷：在短短13个月内，高效完成了560个复杂TPD化合物的合成与交付，成功助力客户快速锁定临床前候选化合物（PCC）。据内部统计，这一速度在当时显著快于行业平均水平。随后三个月内，团队又彻底打通了该PCC的不对称合成路线，并成功交付了约250克的多批次PCC化合物用于药效研究。

此后，该项目无缝对接至药明康德原料药研发及生产服务团队，全面进入Non-GMP与GMP级别的生产阶段。

在整个项目推进过程中，即便未知挑战接踵而至，团队始终与客户保持紧密沟通，并以高效执行力回应每一次需求。“几乎所有客户的问题，RCS团队都能在24小时内给出回复，并提供可执行的解决方案。”RCS该项目负责人在采访中回忆道。他们并非被动完成任务，而是基于对客户目标的深刻理解，主动优化策略，常常按时甚至提前交付。

这份精益求精的专业态度，以及“客户第一”的服务信念，给客户留下了深刻印象。客户随后主动与药明康德就更多项目展开深度合作。在共同探索、试错与突破的过程中，双方逐渐形成了共同成长、发展的长期合作伙伴关系。

图片来源：123RF

从个案到能力：为复杂新型分子铺就通路

这个案例，是药明康德多年来陪伴客户成长、与客户共同前行的又一缩影。在陪伴众多客户成长发展的过程中，药明康德也深度参与了包括PROTACs在内的TPD疗法从概念到产业转化的全过程，并凭借一体化、端到端的CRDMO平台，持续助力全球合作伙伴的这类药物分子完成从发现、开发到生产交付的全周期旅程。

如今，在TPD领域，药明康德RCS团队依托成熟的发现化学平台，已构建起覆盖早期研究支持、毫克级到百克级快速合成与路线优化的综合能力体系。围绕双功能性靶向蛋白降解分子、分子胶等多类降解剂，RCS团队拥有超过1100名化学家，具备连接子、E3泛素连接酶配体以及靶蛋白配体的丰富合成与优化经验，已累计合成超过20万个相关化合物，为复杂分子的快速迭代提供了坚实的化合物库基础；同时，团队建立了丰富的配体与前体库存，可显著提升早期探索的效率与成功率。

针对TPD分子的分离纯化挑战，药明康德组建专门团队深耕此领域，十余年间累计完成超过20万个相关分子的分离工作，建立了完善的分离体系和多样化的方法储备。结合高效的分析纯化体系，包括200余种制备型高效液相色谱（Prep-HPLC）与超临界流体色谱（SFC）方法，以及质谱驱动的三元复合物确认与蛋白组学分析能力，RCS能够支持从化学可行性验证到功能机制研究的关键环节。此外，通过与DMPK及体内外评估能力的协同整合，团队可针对降解剂分子量大、溶解度与稳定性挑战等特性，提供定制化解决方案，帮助客户加速将创新降解策略转化为可推进的候选药物。

这个案例，也正是药明康德践行“跟随科学、跟随客户、跟随分子”理念的生动注脚。不仅是TPD领域，在更广泛的新型疗法持续涌现的新分子浪潮中，药明康德始终与科学同行、与客户并肩，持续夯实平台能力和规模，更好地赋能全球合作伙伴，让创新疗法更快走向病患。如需了解药明康德研发化学服务或业务咨询，请点击文末“阅读原文”

How WuXi AppTec Built a Scalable TPD Platform From a Tough Client Challenge

Drug discovery is a journey into the unknown, where some of its most meaningful moments come not at the finish line, but along the way — as scientists keep pushing through uncertainty and setbacks.

When an unprecedented molecular structure emerges, it brings both the possibility of a breakthrough and a new set of challenges. Turning that possibility into reality takes more than a moment of scientific inspiration. It requires persistence, ingenuity, and the ability to solve one difficult problem after another over the course of a long development journey.

Years ago, a client approached WuXi AppTec’s Research Chemistry Services (RCS) with an unusual hit molecule. It had a high molecular weight and an unconventional structure, and belonged to a class that would later become one of the industry’s most closely watched areas of research: proteolysis-targeting chimeras (PROTACs). Rather than directly inhibiting protein activity like conventional small molecules, PROTACs harness the cell’s ubiquitin–proteasome system to selectively tag and degrade disease-causing proteins. This distinctive mechanism offers the potential to address targets historically considered “undruggable.” At the same time, their size, complex structures and unusual physicochemical properties pose new challenges for synthesis and development.

At the time, targeted protein degradation (TPD) was still nascent. Only a handful of companies and research institutions were exploring PROTACs. Established technical precedents were scarce, and no product had yet completed the full journey from research and development to commercial manufacturing. The path ahead was clearly filled with risk and uncertainty. At the project kickoff, the client put it plainly: “This project is hard to do.”

Tackling a Tough Challenge: 13 Months, 560 Molecules

Faced with challenges that were difficult to anticipate in advance, the WuXi AppTec RCS team chose to tackle them head-on. Following a systematic assessment, the team quickly identified two major technical hurdles: synthesis and purification. Work then began to find practical solutions to both.

On the synthesis side, the client’s initial route suffered from low yields, involved cumbersome steps, and could not support subsequent scale-up. Given this completely new chemotype and the lack of established precedent, the team effectively had to build a route from the ground up. Through iterative experimentation and by drawing on electrochemistry, photochemistry and flow chemistry platforms, they established a more streamlined synthetic route with substantially improved yields. Importantly, the route was also successfully applied to subsequent scale-up, laying a solid foundation for the program to move forward efficiently.

Purification posed a different set of obstacles. The molecule had extremely poor solubility and was unstable under basic conditions, resulting in very low recovery using conventional separation protocols. Through independent process development, the team adopted a “continuous separation coupled with rapid acid neutralization” strategy to stabilize the target compound in real time. The adjustment may have appeared relatively small, but it markedly improved both purity and recovery.

With breakthroughs in both synthesis and purification, the team delivered results that exceeded the client’s expectations. In just 13 months, they synthesized and delivered 560 complex TPD compounds, enabling rapid selection of a preclinical candidate (PCC). This pace was well above the industry average at the time. Over the following three months, they fully established an asymmetric synthetic route for the selected PCC and delivered approximately 250 grams across multiple batches to support efficacy studies.

The program was then handed over seamlessly to WuXi AppTec’s API development and manufacturing team, where it moved into non-GMP and GMP manufacturing.

Throughout the project, new and unexpected challenges continued to emerge. The team maintained close communication with the client and responded rapidly. “The RCS team could respond to almost every client question within 24 hours and provide an actionable solution,” the RCS project lead recalled. The team did more than simply execute assigned tasks. With a clear understanding of the client’s goals, it proactively adjusted and refined project strategies, consistently delivering on time or even ahead of schedule.

The client took notice and subsequently expanded the scope of collaboration to include additional projects. Over time, the two sides moved from individual engagements to a long‑term partnership built around shared growth.

Image source: 123RF

From a Single Case to Platform Capability: Building Pathways for Complex New Modalities

This case exemplifies WuXi AppTec’s long-standing model of collaborating closely with clients and building capabilities alongside their project needs. By supporting the growth and development of numerous partners, the company has been deeply involved in the entire evolution of TPD therapies—including PROTACs—from early concept to industrial translation. Leveraging its integrated, end-to-end CRDMO platform, WuXi AppTec continues to support global partners to take these therapeutic molecules from discovery and development through to manufacturing and delivery.

Today, in the TPD field, the WuXi AppTec RCS team, drawing on a mature discovery chemistry platform, has built a comprehensive set of capabilities that spans early research support, rapid synthesis from milligrams to hundreds of grams, and route optimization. Across bifunctional targeted protein degradation molecules, molecular glues and other types of degraders, the RCS team has more than 1,100 chemists with extensive experience in the synthesis and optimization of linkers, E3 ubiquitin ligase ligands and target protein ligands. To date, they have synthesized more than 230,000 related compounds, providing a robust compound library foundation for rapid iteration of complex molecules. At the same time, the team has built an extensive inventory of ligands and precursors, significantly boosting the efficiency and success rate of early discovery.

WuXi AppTec has also established a dedicated team to address the purification challenges associated with TPD molecules. Over more than a decade, the team has completed separation work for over 200,000 related molecules, establishing a comprehensive separation system and a diverse portfolio of methods. RCS has an efficient analytical and purification system comprising more than 200 preparative high-performance liquid chromatography (Prep-HPLC) and supercritical fluid chromatography (SFC) methods, plus mass spectrometry-based ternary complex confirmation and proteomics analysis capabilities. Collectively, these resources support key steps from chemical feasibility verification to mechanism-of-action studies. In addition, through close integration with DMPK and in vitro/in vivo evaluation capabilities, the team can provide customized solutions for degraders with characteristics such as high molecular weight and challenges related to solubility and stability, helping clients accelerate the translation of innovative degradation strategies into viable drug candidates.

This case also offers a vivid illustration of WuXi AppTec’s philosophy of “following the science, following the client, and following the molecule.” And that philosophy extends beyond TPD. As novel therapeutic modalities continue to generate increasingly diverse and complex molecules, WuXi AppTec continues to advance alongside the science and work side by side with its clients—strengthening its platform capabilities and scale to better support global partners and help bring innovative therapies to patients faster. For more information about WuXi AppTec’s Research Chemistry Services or business collaboration inquiries, please click “Read More” at the end of this article.

Key messages:

• When a client brought WuXi AppTec’s RCS team an unusually complex PROTAC candidate at a time when TPD was still at an early stage, the team overcame major synthesis and purification hurdles and, within just 13 months, delivered over 560 TPD compounds, enabling the rapid nomination of a PCC ahead of industry norms.

• The team maintained close communication throughout the project, responding to almost every client question within 24 hours with actionable solutions. By understanding the client’s objectives and proactively refining project strategies, the team frequently delivered on time or ahead of schedule, helping turn an individual project into a long-term partnership.

• Through supporting many clients as the TPD field has evolved, WuXi AppTec has participated in the journey of TPD modalities from early concepts toward industrial translation. Its integrated, end-to-end CRDMO platform supports these molecules across discovery, development, manufacturing, and delivery.

• In TPD, WuXi AppTec’s RCS team operates on a mature discovery chemistry platform, providing early research support, rapid synthesis from milligram to hectogram scale, and route optimization. A dedicated team with over a decade of experience has completed separations for more than 200,000 related compounds, building a diverse toolkit of separation systems and methods tailored to TPD molecules.