Vepdegestrant

编者按：2025年诺贝尔奖即将在下周揭晓。作为全球科学研究领域的至高荣誉之一，诺贝尔奖已走过一个多世纪，见证了无数推动人类文明进步的伟大突破。从基础科学的前沿探索到造福患者的临床应用，许多获奖成果已成为现代医学发展的基石，催生出改变疾病治疗格局的创新疗法。在这些成就中，泛素介导的蛋白降解机制的发现堪称里程碑，不仅深化了我们对细胞内蛋白稳态调控的理解，也直接催生了一类创新药物——靶向蛋白降解（TPD）疗法，为靶向“不可成药”靶点提供了新策略。如今，首款蛋白降解靶向嵌合体（PROTAC®）药物有望获批上市。值得一提的是，近10年前，在PROTAC®技术刚刚起步之时，药明康德就开始布局相关的能力和技术，并积累了大量成功经验。随着近年来对PROTAC®了解的逐步深入，公司针对这类创新分子已搭建了完善的一体化赋能平台，集发现、合成、分析纯化和测试等能力于一体，目前已成功支持超过120款PROTAC®分子的开发，其中超过20个分子顺利推进至临床阶段。在今天的文章中，我们将回顾泛素介导的蛋白降解如何从实验室走向临床，从基础研究转化为惠及人类健康的现实成果。 细胞天然的“回收系统” 2004年，诺贝尔委员会将化学奖授予三位发现“泛素介导的蛋白降解系统”的科学家——Avram Hershko教授、他曾经的学生Aaron Ciechanover教授以及合作者Irwin Rose教授。 图片来源：The Nobel Prize in Chemistry 2004，NobelPrize.org  人类有数万条编码蛋白的基因。长期以来，研究重点多集中于基因如何指导蛋白合成以及蛋白的功能。而蛋白如何降解却鲜有人关注。 早在1942年，就有研究利用同位素示踪表明动物体内的蛋白质不断合成与降解，始终保持动态平衡。11年后，科学家们进一步发现，大部分细胞内蛋白降解需要消耗额外能量，意味着这一过程受到严格调控。 上世纪七、八十年代之交，一系列开创性研究奠定了这一蛋白降解系统的发现基础。研究人员们发现，网织红细胞裂解液经分离后需两部分混合方能发生依赖能量的蛋白降解：其中一部分含有能与其他蛋白共价结合的泛素；另一部分则包含蛋白酶体复合体和关键的E1、E2、E3三类酶。随着这些分子的逐步揭示，一个完整的蛋白降解系统雏形浮现。 泛素仅由76个氨基酸组成，序列高度保守，广泛存在于真核生物中。如今我们知道，在ATP的作用下，泛素会被激活，先形成泛素-腺苷酸复合物，再被转移到泛素活化酶E1上；随后，E1将活化的泛素转移到泛素结合酶E2上；最终，泛素连接酶E3将泛素转移到目标蛋白上，就像是打上“清除”的标签。这些被打上标签的目标蛋白，也会被送到蛋白酶体复合体处进行降解。 ▲泛素介导的蛋白降解过程和不同的E3泛素连接酶类型（图片来源：参考资料[3]） 这一系统对于真核生物而言不可或缺。它不但能控制细胞周期，还与癌症和免疫系统功能密切相关。可以想象，它也顺理成章地成为了许多药物研发人员眼中的目标。诺贝尔化学奖的新闻稿里富有前瞻性地指出，基于这一系统开发的药物“能启动摧毁不想要的蛋白”，从而治疗多种疾病。 从泛素介导蛋白降解到PROTAC® 这一发现迅速启发科学家探索治疗潜力，耶鲁大学的Craig Crews教授就是先驱者之一。1998年，他与加州理工学院的Raymond Deshaies教授在华盛顿州的一场学术会议中初次见面。两位科学家的思维火花碰撞带来了一个大胆的设想：如果能给致病蛋白打上标签，并送入细胞内的“回收系统”清除，就能达到治疗疾病的目的。更重要的是，这一策略有望攻克传统方法难以触及的“不可成药”靶点——而人类已知的致病蛋白中，超过90%尚未被现有疗法覆盖。 2001年，两位教授合作发表了具有里程碑意义的论文，他们设计了一种人造分子：一端是能够结合目标蛋白的小分子，另一端则是能结合E3连接酶的多肽。研究发现，这种人造分子能将目标蛋白“拉拽”到E3连接酶附近，利用泛素介导的蛋白降解系统进行降解。 “未来，这一方法有望用于诱导蛋白在特定条件下失活，以及降解导致疾病的蛋白。”该论文的摘要里写道。这一分子也被命名为蛋白靶向嵌合分子-1（protein-targeting chimeric molecule 1），缩写为Protac-1。然而基于多肽的设计分子量过大，细胞膜通透性和效力不足，限制了成药潜力。 为了克服这些难点，研究人员们转而思考使用小分子来进行靶向蛋白降解的可能。2008年，首款具有这一特性的小分子诞生。这款小分子一端是雄激素受体的配体，能够选择性地结合雄激素受体。它的另一端则能够结合一种叫做MDM2的E3连接酶。两端之间，则由基于PEG的连接子进行连接。实验表明，该分子能够将雄激素受体招募到MDM2附近，使其泛素化，并随之被蛋白酶体复合体降解。这种能够诱导靶向蛋白降解的嵌合分子，也被命名为PROTAC®（PROteolysis TArgeting Chimera）。 厚积薄发，PROTAC®浪潮已至 2013年，Crews教授联合创立Arvinas公司，加速这一技术的科学转化。为了测试此类分子的成药可行性，该公司优先选择雄激素受体和雌激素受体这两个比较成熟的靶点。2019年，首个PROTAC®分子的论文发布后的18年，Arvinas公司的两款候选疗法首次挺进临床试验阶段，并于次年获得临床概念验证。2021年，Arvinas进一步公布积极数据，靶向降解雌激素受体的ARV-471可将患者肿瘤组织中的雌激素受体表达水平平均降低62%。同年，辉瑞（Pfizer）与Arvinas达成超20亿美元的研发合作，共同打造这款PROTAC®分子。 这款PROTAC®疗法今年迎来关键里程碑。今年8月，Arvinas与辉瑞宣布，美国FDA已接受为vepdegestrant（曾名为ARV-471）递交的新药申请（NDA），预计在明年6月之前完成审评。如果获批，该药将成为首款获批的PROTAC®疗法。 在Arvinas开发的PROTAC®分子获得临床概念验证之后，靶向蛋白降解领域成为新药开发的热点。截至2025年9月，业内已有120多款在研蛋白降解疗法处于临床开发阶段。 CRDMO一体化赋能蛋白降解疗法开发 长期以来，药明康德支持全球合作伙伴从药物研究（R）、开发（D）到商业化生产（M）各个阶段的需求，通过独特的一体化、端到端CRDMO模式，助力突破性疗法加速研发进程、早日惠及患者。 在靶向蛋白降解疗法近10年的产业转化历程中，药明康德几乎全程参与，为合作伙伴提供一体化赋能。在PROTAC®刚刚起步时，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，助力全球合作伙伴高效推进药物从早期发现到临床试验阶段。伴随着新型靶向蛋白降解技术的持续涌现，药明康德紧跟科学前沿，迅速构建相关技术平台，如今能力已涵盖PROTAC®、分子胶、AUTAC、LYTAC、DUBTAC、RIBOTAC、PHICS以及DAC等主要分子类型。 迄今为止，药明康德已与150多家公司在靶向蛋白降解化合物开发的各个阶段开展合作，全球每三家开发靶向蛋白降解候选药物的公司中，就有两家是药明康德的合作伙伴。在赋能全球客户的过程中，药明康德已合成了超过18.8万种复杂的靶向蛋白降解化合物，其中70多种已进入临床前候选药物阶段，10多种已进入后期开发阶段。 在近期接受行业媒体STAT采访时，药明康德联席首席执行官杨青博士指出：“药明康德致力于支持全球客户加速研发进程，从小型和新锐生物技术公司（biotech）到大型药企，我们的CRDMO平台能够‘端到端’助力靶向蛋白降解分子从发现、到开发，再到生产交付的全过程。凭借全面综合的能力，我们能将有潜力的创新想法高效、高质量地转化为现实。” 结语 从2004年泛素介导的蛋白降解研究斩获诺贝尔化学奖，到今天首款PROTAC®疗法距上市一步之遥，这段历程凝聚了科学与产业界无数人的坚持与创新。药明康德也有幸全程见证这段旅程，并为全球靶向蛋白降解的创新者提供赋能。展望未来，药明康德将继续依托独特的一体化、端到端CRDMO平台，助力合作伙伴解锁靶向蛋白降解的更多可能，为全球癌症和其他疾病患者带来新的希望！ Drugging the “Undruggable”: Nobel-Winning Research Sparks a New Treatment Modality The 2025 Nobel Prizes are about to be announced next week. As one of the top honors in global scientific research, the Nobel Prize has spanned more than a century, celebrating countless breakthroughs that have propelled human civilization forward. From pioneering discoveries in basic science to clinical applications that improve patients’ lives, many Nobel-winning achievements have become cornerstones of modern medicine. Among these milestones, the discovery of the ubiquitin-mediated protein degradation mechanism stands out. It not only deepened our understanding of intracellular protein homeostasis, but also directly gave rise to a new class of medicines—targeted protein degradation therapies (TPD). Today, the first proteolysis-targeting chimera (PROTAC®) therapy is nearing potential approval, offering real hope to patients worldwide. Nearly a decade ago, when PROTAC® technology was still in its infancy, WuXi AppTec began building relevant capabilities. Since then, the company has established a comprehensive, integrated platform encompassing discovery, synthesis, purification, analysis, and testing. To date, WuXi AppTec has supported the development of more than 120 PROTAC® molecules, with over 20 advancing into clinical trials. This article reviews how ubiquitin-mediated protein degradation evolved from a laboratory discovery into clinical reality, transforming basic research into tangible benefits for human health. The Cell’s Natural "Recycling System" In 2004, the Nobel Committee awarded the Chemistry Prize to three scientists for their discovery of the “ubiquitin-mediated protein degradation system”—Professor Avram Hershko, his former student Professor Aaron Ciechanover, and collaborator Professor Irwin Rose. Humans carry tens of thousands of protein-coding genes. For decades, research focused heavily on how genes direct protein synthesis and how proteins function, while the question of how proteins are degraded received relatively little attention. This began to change in 1942, when isotopic tracing experiments revealed that proteins in animals underwent continuous synthesis and degradation, maintaining dynamic equilibrium. Eleven years later, scientists discovered that most protein degradation in cells requires additional energy, suggesting that the process is actively regulated rather than random. By the late 1970s and early 1980s, a series of groundbreaking studies laid the foundation for uncovering this system. Researchers showed that reticulocyte lysates, once fractionated, required recombination of two fractions to achieve energy-dependent protein degradation. One contained ubiquitin, which could covalently attach to many other proteins; the other contained the proteasome complex as well as the key enzymes E1, E2, and E3. As these components were identified, the outlines of a complete degradation system began to emerge. Ubiquitin, a small protein of just 76 amino acids, has a highly conserved sequence and is widely present in eukaryotes. We now know that ubiquitin is activated, transferred sequentially through E1 and E2 enzymes, and ultimately attached to target proteins by an E3 ligase—essentially tagging them for destruction. These tagged proteins are then directed to the proteasome complex for degradation. This system is indispensable for eukaryotic life. It not only governs the cell cycle, but is also closely linked to cancer and immune function. Unsurprisingly, it quickly became a compelling target for drug development. The Nobel Prize press release at the time foresaw this potential, noting that drugs based on the system could “trigger the destruction of unwanted proteins” and thereby treat many diseases. From Ubiquitin-Mediated Degradation to PROTAC® The discovery soon inspired scientists to explore therapeutic applications, with Professor Craig Crews of Yale University among the pioneers. In 1998, at a scientific meeting in Washington state, Crews met Professor Raymond Deshaies of the California Institute of Technology. Their discussion sparked a bold idea: if disease-causing proteins could be tagged and routed into the cell’s "recycling system," they might be selectively eliminated, paving the way for powerful new treatments. Even more significantly, this approach promised to address the vast majority of disease-related proteins that remain beyond the reach of traditional drug discovery methods. In 2001, Crews and Deshaies published a landmark paper describing a synthetic molecule with two functional ends: one bound to a target protein, the other to an E3 ligase. This construct successfully brought the target protein into proximity with the ligase, inducing its degradation via the ubiquitin pathway. The authors noted that the method might one day enable conditional protein inactivation and selective destruction of disease-causing proteins. They named the construct protein-targeting chimeric molecule 1 (Protac-1). However, because Protac-1 was peptide-based, it was large and had poor cell permeability, limiting its clinical application. To overcome these challenges, researchers explored small-molecule solutions. In 2008, the first such molecule was reported. One end selectively bound the androgen receptor, while the other engaged the E3 ligase MDM2, with the two connected by a PEG linker. Experiments confirmed that the molecule successfully induced ubiquitination and degradation of the androgen receptor. This new class of bifunctional degraders was formally named PROTAC® (PROteolysis TArgeting Chimera). The PROTAC® Wave Arrives In 2013, Crews co-founded Arvinas to accelerate the translation of PROTAC® technology into medicines. To demonstrate feasibility, the company focused first on two established targets: the androgen receptor and the estrogen receptor. By 2019, two candidates had entered clinical trials, achieving proof of concept the following year. In 2021, Arvinas released promising data showing that its estrogen receptor degrader ARV-471 reduced receptor expression in patient tumor tissue by an average of 62%. That same year, Pfizer entered into a collaboration with Arvinas to co-develop the therapy. This program reached a critical milestone in August 2025, when Arvinas and Pfizer announced that the U.S. FDA had accepted the New Drug Application (NDA) for vepdegestrant (formerly ARV-471). Regulatory review is expected to conclude by June 2026. If approved, it would become the first PROTAC® therapy to reach the market. Arvinas’ clinical proof of principle ignited a wave of interest in targeted protein degradation across the biopharma industry. By September 2025, more than 120 protein degrader therapies were in clinical development worldwide. Integrated CRDMO Platform Enables Protein Degrader Development For years, WuXi AppTec has supported partners worldwide across discovery, development, and manufacturing through its unique integrated, end-to-end CRDMO model, accelerating the advancement of breakthrough therapies to patients. From the earliest days of PROTAC®, the company strategically invested in relevant technologies, building a platform that integrates discovery, synthesis, purification, and testing to help global partners efficiently advance programs from early-stage research into clinical trials. As new modalities—including molecular glues, AUTAC, LYTAC, DUBTAC, RIBOTAC, PHICS, and DAC—have emerged, WuXi AppTec has rapidly expanded its capabilities to remain at the cutting edge of science. Today, WuXi AppTec has partnered with more than 150 companies on all stages in development of targeted protein degrader compounds, working with two out of every three companies developing TPD candidates. We have synthesized more than 188,000 complex targeted protein degrader compounds, with more than 70 advancing to preclinical candidate (PCC) status and over 10 entering late-stage development. In a recent interview with STAT, Dr. Steve Yang, Co-CEO of WuXi AppTec, emphasized: “WuXi AppTec supports customers from small and emerging biotechs to large pharmas in advancing their pioneering TPD projects across all stages of our CRDMO platform — from discovery to development and delivery. These comprehensive capabilities enable us to help transform promising ideas into reality with speed and quality.” From the 2004 Nobel Prize in Chemistry honoring the discovery of ubiquitin-mediated protein degradation to the potential approval of the first PROTAC® therapy, this journey reflects the perseverance and innovation of scientists and industry leaders worldwide. WuXi AppTec has been privileged to witness and contribute to this history, empowering innovators in targeted protein degradation at every step. Looking ahead, the company will continue leveraging its integrated, end-to-end CRDMO platform to unlock new possibilities and bring transformative therapies to patients with cancer and other diseases worldwide. 参考资料： [1] Ubiquitin-mediated proteolysis, Retrieved July 28, 2021, from https://www.nobelprize.org/uploads/2018/06/advanced-chemistryprize2004.pdf [2] Proteins labelled for destruction. Retrieved September 11, 2025, from https://www.nobelprize.org/prizes/chemistry/2004/press-release/ [3] Hinterndorfer et al., (2025). Targeted protein degradation for cancer therapy. Nature Reviews Cancer, https://doi.org/10.1038/s41568-025-00817-8 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新