同行致遠 | 從摘得諾獎到首款新藥有望上市，創新治療模式劍指“不可成藥”靶點 | Bilingual

編者按：2025年諾貝爾獎即將在下周揭曉。作為全球科學研究領域的至高榮譽之一，諾貝爾獎已走過一個多世紀，見證了無數推動人類文明進步的偉大突破。從基礎科學的前沿探索到造福患者的臨床應用，許多獲獎成果已成為現代醫學發展的基石，催生出改變疾病治療格局的創新療法。在這些成就中，泛素介導的蛋白降解機制的發現堪稱里程碑，不僅深化了我們對細胞內蛋白穩態調控的理解，也直接催生了一類創新藥物——靶向蛋白降解（TPD）療法，為靶向“不可成藥”靶點提供了新策略。如今，首款蛋白降解靶向嵌合體（PROTAC?）藥物有望獲批上市。值得一提的是，近10年前，在PROTAC?技術剛剛起步之時，藥明康德就開始布局相關的能力和技術，并積累了大量成功經驗。隨著近年來對PROTAC?了解的逐步深入，公司針對這類創新分子已搭建了完善的一體化賦能平臺，集發現、合成、分析純化和測試等能力于一體，目前已成功支持超過120款PROTAC?分子的開發，其中超過20個分子順利推進至臨床階段。在今天的文章中，我們將回顧泛素介導的蛋白降解如何從實驗室走向臨床，從基礎研究轉化為惠及人類健康的現實成果。

細胞天然的“回收系統”

2004年，諾貝爾委員會將化學獎授予三位發現“泛素介導的蛋白降解系統”的科學家——Avram Hershko教授、他曾經的學生Aaron Ciechanover教授以及合作者Irwin Rose教授。

圖片來源：The Nobel Prize in Chemistry 2004，NobelPrize.org

人類有數萬條編碼蛋白的基因。長期以來，研究重點多集中于基因如何指導蛋白合成以及蛋白的功能。而蛋白如何降解卻鮮有人關注。

早在1942年，就有研究利用同位素示蹤表明動物體內的蛋白質不斷合成與降解，始終保持動態平衡。11年后，科學家們進一步發現，大部分細胞內蛋白降解需要消耗額外能量，意味著這一過程受到嚴格調控。

上世紀七、八十年代之交，一系列開創性研究奠定了這一蛋白降解系統的發現基礎。研究人員們發現，網織紅細胞裂解液經分離后需兩部分混合方能發生依賴能量的蛋白降解：其中一部分含有能與其他蛋白共價結合的泛素；另一部分則包含蛋白酶體復合體和關鍵的E1、E2、E3三類酶。隨著這些分子的逐步揭示，一個完整的蛋白降解系統雛形浮現。

泛素僅由76個氨基酸組成，序列高度保守，廣泛存在于真核生物中。如今我們知道，在ATP的作用下，泛素會被激活，先形成泛素-腺苷酸復合物，再被轉移到泛素活化酶E1上；隨后，E1將活化的泛素轉移到泛素結合酶E2上；最終，泛素連接酶E3將泛素轉移到目標蛋白上，就像是打上“清除”的標簽。這些被打上標簽的目標蛋白，也會被送到蛋白酶體復合體處進行降解。

▲泛素介導的蛋白降解過程和不同的E3泛素連接酶類型（圖片來源：參考資料[3]）

這一系統對于真核生物而言不可或缺。它不但能控制細胞周期，還與癌癥和免疫系統功能密切相關。可以想象，它也順理成章地成為了許多藥物研發人員眼中的目標。諾貝爾化學獎的新聞稿里富有前瞻性地指出，基于這一系統開發的藥物“能啟動摧毀不想要的蛋白”，從而治療多種疾病。

從泛素介導蛋白降解到PROTAC?

這一發現迅速啟發科學家探索治療潛力，耶魯大學的Craig Crews教授就是先驅者之一。1998年，他與加州理工學院的Raymond Deshaies教授在華盛頓州的一場學術會議中初次見面。兩位科學家的思維火花碰撞帶來了一個大膽的設想：如果能給致病蛋白打上標簽，并送入細胞內的“回收系統”清除，就能達到治療疾病的目的。更重要的是，這一策略有望攻克傳統方法難以觸及的“不可成藥”靶點——而人類已知的致病蛋白中，超過90%尚未被現有療法覆蓋。

2001年，兩位教授合作發表了具有里程碑意義的論文，他們設計了一種人造分子：一端是能夠結合目標蛋白的小分子，另一端則是能結合E3連接酶的多肽。研究發現，這種人造分子能將目標蛋白“拉拽”到E3連接酶附近，利用泛素介導的蛋白降解系統進行降解。

“未來，這一方法有望用于誘導蛋白在特定條件下失活，以及降解導致疾病的蛋白。”該論文的摘要里寫道。這一分子也被命名為蛋白靶向嵌合分子-1（protein-targeting chimeric molecule 1），縮寫為Protac-1。然而基于多肽的設計分子量過大，細胞膜通透性和效力不足，限制了成藥潛力。

為了克服這些難點，研究人員們轉而思考使用小分子來進行靶向蛋白降解的可能。2008年，首款具有這一特性的小分子誕生。這款小分子一端是雄激素受體的配體，能夠選擇性地結合雄激素受體。它的另一端則能夠結合一種叫做MDM2的E3連接酶。兩端之間，則由基于PEG的連接子進行連接。實驗表明，該分子能夠將雄激素受體招募到MDM2附近，使其泛素化，并隨之被蛋白酶體復合體降解。這種能夠誘導靶向蛋白降解的嵌合分子，也被命名為PROTAC?（PROteolysis TArgeting Chimera）。

厚積薄發，PROTAC?浪潮已至

2013年，Crews教授聯合創立Arvinas公司，加速這一技術的科學轉化。為了測試此類分子的成藥可行性，該公司優先選擇雄激素受體和雌激素受體這兩個比較成熟的靶點。2019年，首個PROTAC?分子的論文發布后的18年，Arvinas公司的兩款候選療法首次挺進臨床試驗階段，并于次年獲得臨床概念驗證。2021年，Arvinas進一步公布積極數據，靶向降解雌激素受體的ARV-471可將患者腫瘤組織中的雌激素受體表達水平平均降低62%。同年，輝瑞（Pfizer）與Arvinas達成超20億美元的研發合作，共同打造這款PROTAC?分子。

這款PROTAC?療法今年迎來關鍵里程碑。今年8月，Arvinas與輝瑞宣布，美國FDA已為vepdegestrant（曾名為ARV-471）遞交的新藥申請（NDA），預計在明年6月之前完成審評。如果獲批，該藥將成為首款獲批的PROTAC?療法。

在Arvinas開發的PROTAC?分子獲得臨床概念驗證之后，靶向蛋白降解領域成為新藥開發的熱點。截至2025年9月，業內已有120多款在研蛋白降解療法處于臨床開發階段。

CRDMO一體化賦能蛋白降解療法開發

長期以來，藥明康德支持全球合作伙伴從藥物研究（R）、開發（D）到商業化生產（M）各個階段的需求，通過獨特的一體化、端到端CRDMO模式，助力突破性療法加速研發進程、早日惠及患者。

在靶向蛋白降解療法近10年的產業轉化歷程中，藥明康德幾乎全程參與，為合作伙伴提供一體化賦能。在PROTAC?剛剛起步時，藥明康德就前瞻性地布局了相關能力和技術，搭建了集發現、合成、分析純化和測試等能力于一體的一體化賦能平臺，助力全球合作伙伴高效推進藥物從早期發現到臨床試驗階段。伴隨著新型靶向蛋白降解技術的持續涌現，藥明康德緊跟科學前沿，迅速構建相關技術平臺，如今能力已涵蓋PROTAC?、分子膠、AUTAC、LYTAC、DUBTAC、RIBOTAC、PHICS以及DAC等主要分子類型。

迄今為止，藥明康德已與150多家公司在靶向蛋白降解化合物開發的各個階段開展合作，全球每三家開發靶向蛋白降解候選藥物的公司中，就有兩家是藥明康德的合作伙伴。在賦能全球客戶的過程中，藥明康德已合成了超過18.8萬種復雜的靶向蛋白降解化合物，其中70多種已進入臨床前候選藥物階段，10多種已進入后期開發階段。

在近期接受行業媒體時，藥明康德聯席首席執行官楊青博士指出：“藥明康德致力于支持全球客戶加速研發進程，從小型和新銳生物技術公司（biotech）到大型藥企，我們的CRDMO平臺能夠‘端到端’助力靶向蛋白降解分子從發現、到開發，再到生產交付的全過程。憑借全面綜合的能力，我們能將有潛力的創新想法高效、高質量地轉化為現實。”

結語

從2004年泛素介導的蛋白降解研究斬獲諾貝爾化學獎，到今天首款PROTAC?療法距上市一步之遙，這段歷程凝聚了科學與產業界無數人的堅持與創新。藥明康德也有幸全程見證這段旅程，并為全球靶向蛋白降解的創新者提供賦能。展望未來，藥明康德將繼續依托獨特的一體化、端到端CRDMO平臺，助力合作伙伴解鎖靶向蛋白降解的更多可能，為全球癌癥和其他疾病患者帶來新的希望！

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.

參考資料：

[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

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