靶向蛋白降解 (TPD) 是一種創新療法，它基于細胞自身的蛋白質清除機制，能夠選擇性地降解致病蛋白，對治療難治性癌癥和其他疾病具有非凡的潛力。

近期，這是一款潛在的“first-in-class”口服PROTAC?（蛋白水解靶向嵌合體，一種TPD），用于針對特定的乳腺癌患者。如果獲得批準，這將意味著一種突破性療法的問世，有望在未來改寫許多疾病的治療方式。

作為全球化CRDMO平臺，藥明康德早在此類新分子剛剛起步之時，就前瞻性地布局了相關能力和技術，并積累了大量成功經驗。迄今為止，藥明康德已與150多家公司在TPD化合物開發的各個階段開展合作，全球每三家開發TPD候選藥物的公司中，就有兩家是藥明康德的合作伙伴。

?TPD療法為何具有突破性？

?開發TPD療法有哪些困難和挑戰？

?藥明康德如何助力PROTAC及其他TPD療法的研發？

?對創新藥企而言，找對合作伙伴到底有多重要？

近日，藥明康德聯席首席執行官楊青博士與權威行業媒體STAT對談，分享了他對TPD如何改寫癌癥和其他疾病治療前景的洞見，并對一體化CRDMO平臺在加速此類藥物研發方面的作用進行了深度解讀。

以下是對話全文。

STAT：在您看來，為什么靶向蛋白降解（TPD）療法如此具有突破性？

楊青博士：以PROTAC?為代表的TPD療法的突破性在于，其能夠打破傳統小分子藥物的局限，從而克服此前被認為“不可成藥”的靶點。

自PROTAC?技術問世以來，研究人員已經利用相似的（誘導接近）策略，開發出多種創新TPD結構，包括AUTAC（自噬靶向嵌合小分子）、LYTAC（溶酶體靶向嵌合體）和RIPTAC（調節誘導接近靶向嵌合體）等。它們通過連接不同功能的分子，從而產生組合治療的效果。這些新方法在治療癌癥、神經系統疾病和其他疑難病癥方面展現出了巨大的潛力。

STAT：在助力TPD療法從創新概念走向臨床驗證的過程中，藥明康德扮演了怎樣的角色？

楊青博士：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TPD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。

目前，藥明康德已合成了超過188,000種復雜的TPD化合物，其中70多種已進入臨床前候選藥物（PCC）階段，10多種已進入后期開發階段。

STAT：蛋白降解療法通常面臨制劑、穩定性、遞送等方面的挑戰。藥明康德如何應對這些挑戰，助力這些創新療法更快造福患者？

楊青博士：TPD分子結構復雜龐大，的確在合成、靶標結合、穩定性和生物利用度等方面存在多重挑戰。這種復雜性可能會讓許多初創biotech公司難以應對。由于科學家人數、時間和資金等資源有限，biotech公司要想將創新TPD分子推進至下一個里程碑，往往困難重重。

因此，越來越多的新銳公司依賴藥明康德這樣的一體化CRDMO平臺。這樣的好處顯而易見：初創公司無需從零開始自建基礎設施，還能充分依托我們在藥物發現、開發和生產方面的全鏈條經驗。這種合作關系有助于提升研發效率，加速新藥開發進程，控制研發成本，新銳biotech公司可以更加專注于科學創新，同時嚴格保有其核心知識產權（IP）。

STAT：您能否再舉幾個例子，說明這種合作模式是如何運轉的？

楊青博士：當然。之前有一位biotech合作伙伴找到我們，希望我們能夠合成一種復雜的TPD分子，合成步驟達到24步。

我們的一個團隊重新設計了合成路線，將合成步驟縮短了三分之一，并且減少使用了一種昂貴的催化劑。同時，另一個團隊使用并優化噴霧干燥（SDD）技術進行制劑制備，顯著提高生物利用度，為后續臨床應用奠定了堅實的基礎。內部無縫銜接的流程使我們的生產團隊提前兩個月生產出客戶所需。

可以再分享一個例子。有一位客戶找到我們，詢問我們能否完成一項簡直“不可能”的任務：在30天內合成一個復雜的分子。我們立即動員組建了一支由40名化學家組成的“攻堅”小隊，通過接力協作，對多輪放大生產進行實時驗證，大幅簡化流程，最終在短短29天內交付。

這些故事只是藥明康德一體化平臺助力全球創新者加速新藥研發的“冰山一角”而已。

STAT：聽起來，高效的合作和一體化平臺整合對于快速推進此類復雜項目至關重要。如果是一家初創公司，要獨自完成這些工作將極具挑戰性。

楊青博士：確實如此。新藥研發是一場漫長的征程，需要大膽的科學突破，創新轉化也至關重要。從一個概念的提出，到最終真正惠及患者，我們需要的不僅是科學本身，更需要合作、效率和規模。這正是藥明康德一體化平臺所提供的價值。

The End of the Undruggable: Targeted Protein Degradation Therapies Open New Frontiers in Cancer Care

Targeted protein degradation (TPD) therapy is a promising new class of targeted treatments. Based on a cell’s natural mechanism for eliminating diseased proteins, this therapy can combat hard-to-treat cancers and other conditions.

The U.S. Food and Drug Administration is currently reviewing a New Drug Application for vepdegestrant, a pioneering PROTAC? (PROteolysis TArgeting Chimera, a type of TPD) molecule targeting certain breast cancer. The medication, which was developed by Arvinas in partnership with Pfizer, is the first PROTAC? therapy to be submitted for regulatory review. If approved, this treatment would represent a breakthrough approach that could change the way many diseases are treated.

WuXi AppTec, a global Contract Research, Development, and Manufacturing Organization (CRDMO), is one of the most experienced enablers in this space. It 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.

WuXi AppTec Co-CEO Steve Yang offers his perspective on how targeted protein degraders could revolutionize treatment of cancer and other diseases and describes the role that CRDMOs play in speeding development of such drug candidates.

STAT: From your perspective, what makes these therapies so transformative?

Steve Yang:TPDs such as PROTAC?s are designed to break some of the major barriers of traditional small molecule drugs, thus targeting previously “un-druggable” proteins.

Since PROTAC?s were developed, researchers have created several new versions of TPDs —such as AUTACs, LYTACs, and RIPTACs—that use a similar strategy. They all bring two proteins close together to produce a therapeutic effect. These new approaches are showing great promise in treating cancer, neurological diseases, and other difficult health conditions.

STAT: What role has WuXi AppTec played in helping to bring targeted protein degradation from concept to clinic?

Steve Yang: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.

WuXi AppTec has synthesized more than 188,000 complex targeted protein degrader (TPD) compounds, with more than 70 advancing to preclinical candidate (PCC) status and over 10 entering late-stage development.

STAT: Protein degradation therapies often face hurdles with formulation, stability, and delivery. How is your team addressing these obstacles to help make these therapies more viable for patients?

Steve Yang:These molecules are structurally large and intricate, posing challenges in synthesis, target binding, stability, and bioavailability. Such complexity can overwhelm many biotech startups. With only a handful of scientists and limited time and funding, moving a novel degrader toward the next milestone can be daunting.

Early-stage companies are increasingly leaning on integrated CRDMOs like WuXi AppTec. The appeal is clear: rather than build infrastructure from scratch, startups can focus on science and innovation while leveraging our depth in discovery, development, and manufacturing. Such partnerships improve efficiency, speed development and controls costs, while allowing biotechs to focus on scientific innovation and maintain tight control over their IP.

STAT: Can you provide some examples that illustrate how this works?

Steve Yang:Sure. One biotech partner came to us with a complex molecule that required 24 synthetic steps to manufacture. The company came to us to produce enough of that material to hit its next milestone.

One of our teams redesigned the synthesis process, reducing the number of steps by a third and eliminated the need to use a costly catalyst. Another team simultaneously developed a spray-dried dispersion formulation that improved bioavailability to meet the clinical requirement. That seamless collaboration allowed our manufacturing team to produce the required materials two months ahead of schedule.

Another client approached us asking if we could complete an “impossible” assignment: synthesize a complex molecule within 30 days. We mobilized a "SWAT” team of 40 chemists who worked around the clock in rotating shifts. They validated multiple rounds of scale-up in real time, streamlined the processes and delivered the needed material in just 29 days. These are a few examples of how WuXi AppTec’s integrated platform helps accelerate drug development for global innovators.

STAT: Effective collaboration and integration sound critical for advancing such complex projects smoothly and swiftly. It will be challenging for a startup to do that on their own.

Steve Yang:That’s right. In a space defined by long timelines and bold science, translation is everything. From idea to impact, it takes more than science—it takes collaboration, speed, and scale. That’s what we’re here to deliver.

Learn more about how new modalities translate from discovery to delivery: https://www.wuxiapptec.com/platform

免責聲明：本文僅作信息交流之目的，文中觀點不代表藥明康德立場，亦不代表藥明康德支持或反對文中觀點。本文也不是治療方案推薦。如需獲得治療方案指導，請前往正規醫院就診。

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