PROTAC作为一种双功能分子，其一端与靶蛋白结合，另一端与E3泛素连接酶结合，诱导泛素连接酶给靶蛋白打上泛素“标签”，标记它们被送入蛋白酶体降解。这一独特作用机制在靶向“不可成药”的蛋白靶点方面具有多重优势，它无需与靶蛋白上的特定活性位点高亲和力结合，仅通过复合物形成即可引发靶蛋白的降解。此外，蛋白降解为靶向转录因子、骨架蛋白等不依赖酶活性产生生物学作用的靶点提供了新的成药途径，这些蛋白难于被传统小分子抑制剂靶向。

然而，PROTAC药物开发也面临着独特的挑战，其中提高口服生物利用度尤为关键。由于PROTAC分子通常由两个独立配体连接形成，分子体积大且物理化学性质复杂，导致溶解性和口服药代动力学特征不理想。这正是本案例中合作伙伴选择药明康德旗下合全药业（WuXi STA）合作的原因之一。

在该项目中，合作伙伴计划在14个月内完成IND申报所需的PROTAC候选药物的制备，并为首次人体临床研究提供临床试验用药。然而，该分子在化学合成和制剂开发方面均存在困难。在化学合成方面，初始合成路线长达24步，产率仅为0.3%，其中还有三步涉及金属钯（Pd）作为催化剂，导致除Pd工艺复杂，显著提高了生产成本。此外，PROTAC特定的分子结构进一步增加了产品结晶和纯化难度。最初的生产方案需要耗费超过100万美元才能合成1公斤活性药物成分（API），难以支持临床开发。

针对这些挑战，合全药业的工艺研发团队、生物催化技术团队、结晶工艺技术团队等开展了协同攻关。在合成工艺开发方面，化学家与生物催化专家根据在PROTAC领域积累的丰富经验，以使用生物催化剂代替Pd催化剂作为突破口，重新设计了一条合成路线。这条路线将合成步骤从原来的24步减少至16步，并且在其中两个步骤用生物催化剂替代了钯催化剂。为了攻克结晶难题，团队采用了高通量结晶筛选技术，探索满足纯度与收率要求的结晶工艺。根据晶型稳定性和溶解度数据，最终选择两种溶剂体系进行优化，确定了最终结晶工艺。这些改进不但大大提高了整体合成工艺的可放大性，也提升了合成效率并降低了成本。

在制剂开发方面，口服给药由于其便捷性与调整给药方案的灵活性，更容易在临床试验中探索疗效与安全性的平衡。然而，这款PROTAC分子因为分子量大（约800），水溶性极差，导致口服生物利用度仅为0.9%，给开发口服制剂增添了难度。为了解决这一难题，合全药业的制剂研发团队系统性评估了多种生物利用度增强技术，包括喷雾干燥制备固体分散体（SDD）、热熔挤出、纳米研磨和液体胶囊。最终，喷雾干燥技术脱颖而出。该技术将难溶药物以无定形状态高度分散在聚合物中，从而显著增加药物颗粒的表面积/体积比率，提高药物的溶解性。借助对SDD处方组成与工艺的进一步优化，候选化合物片剂的口服生物利用度提升了约30倍，为后续临床应用奠定了坚实基础。

合全药业一体化CDMO平台的整合能力，使多个团队能够并行推进原料药与制剂开发，加速破解PROTAC分子开发过程中的难题。最终，团队仅用12个月就完成了支持IND申请所需的候选药物生产和制剂制备，顺利供应首次人体临床研究用药，比合作伙伴原定时间提前了2个月。

PROTAC领域近期有望迎来重要里程碑，由Arvinas和辉瑞（Pfizer）联合开发的PROTAC药物vepdegestrant在3期临床试验中获得积极结果，两家公司日前已经向美国FDA递交新药申请（NDA）。如果获得批准，它预计将成为首款获得FDA批准的PROTAC疗法。未来，药明康德将继续依托其一体化CRDMO平台，持续赋能合作伙伴包括PROTAC在内的靶向蛋白降解药物开发，将科学创新早日转化成为造福病患的创新药物。

Breaking Through Key Bottlenecks in PROTAC Development

A recent collaboration involved the rapid production of a proteolysis-targeting chimera (PROTAC) candidate, with the goal of submitting an Investigational New Drug (IND) application and delivering clinical trial material for first-in-human (FIH) studies within just 14 months. By leveraging an integrated CMC platform and advanced enabling technologies in both API process development and formulation, WuXi STA’s team successfully delivered the FIH material in just 12 months—two months ahead of schedule.

PROTACs: A Unique Modality with Unique Challenges

Targeted protein degraders (TPDs) eliminate disease-causing proteins by inducing their degradation within cells. Among them, PROTACs are bifunctional molecules that recruit an E3 ubiquitin ligase to a target protein, tagging it with ubiquitin for destruction by the proteasome. This mechanism allows PROTACs to act without requiring high-affinity binding to an active site, offering a compelling strategy to tackle “undruggable” targets.

However, the promise of PROTACs comes with unique development challenges, particularly in enhancing oral bioavailability. Due to their large molecular weight and structural complexity, PROTACs often suffer from poor solubility and suboptimal pharmacokinetics. Recognizing these development hurdles, the partner opted to collaborate with WuXi STA, part of WuXi AppTec, to address the challenges effectively.

In this project, the PROTAC compound presented multiple development challenges. With a molecular weight nearing 800 and poor water solubility that translated to an oral bioavailability of just 0.9%, formulation posed a major hurdle. In addition, the initial synthetic route involved 24 steps and yielded only 0.3%. Three of these steps required palladium (Pd) catalysis, complicating purification due to residual Pd removal and elevating cost. The specific molecular structure of the PROTAC further hindered crystallization and purification. The initial production costs exceeded $1 million for just 1 kilogram of API—an unsustainable cost for clinical development.

Navigating Synthesis and Formulation Hurdles

To address these challenges, WuXi STA’s process development team, biocatalysis team, and crystallization technology team worked collaboratively. Drawing on extensive experience in the PROTAC field, the chemistry and biocatalysis experts redesigned the synthesis route—introducing biocatalytic transformations in place of Pd-catalyzed steps, thereby improving both efficiency and cost-effectiveness.

Crystallization was similarly optimized. The team employed high-throughput crystallization screening to pinpoint processes that met both purity and yield requirements. Based on data from crystal form stability and solubility tests, two solvent systems were selected for further optimization, yielding a robust crystallization process. 

In parallel, WuXi STA’s formulation development team systematically evaluated multiple bioavailability enhancement technologies, including spray-dried dispersions (SDD), hot-melt extrusion, nanomilling, and liquid formulations. SDD emerged as the optimal choice, offering the ability to disperse poorly soluble drugs in an amorphous state within a polymer matrix, significantly increasing the surface area-to-volume ratio and improving dissolution.

Delivering Results: A More Efficient Path to First-in-Human Trial

By leveraging its integrated CMC platform and advanced enabling technologies in both API process development and formulation, WuXi STA developed a more scalable, efficient, and cost-effective manufacturing process. Key achievements included:

• Reducing synthesis steps from 24 to 16, while replacing Pd catalysts with biocatalysts in two steps. 
• Improving the oral bioavailability of the tablet form by approximately 30-fold through SDD optimization, laying a solid foundation for future clinical application.

These advancements, enabled by parallel workflows and close cross-functional collaboration, allowed the team to complete IND-enabling production and formulation ahead of schedule and successfully supply the drug for the first-in-human study within 12 months.

As the field of targeted protein degradation continues to evolve, WuXi STA remains committed to leveraging its integrated CDMO platform to empower the development of targeted protein degraders (including PROTACs), helping partners translate scientific innovation into life-changing medicines for patients around the world.

参考资料：

[1] Advancing targeted protein degraders: leveraging CMC strategies for rapid IND submission and bioavailability solutions. Retrieved June 2, 2025, from https://sta.wuxiapptec.com/wp-content/uploads/2024/10/Advancing-targeted-protein-degraders.pdf

[2] PROTAC protein degraders to drug the undruggable enter phase 3 trials. Retrieved June 2, 2025, from https://www.nature.com/articles/d41591-024-00072-8