同行致遠 | 超過10款新藥獲批上市，“不可成藥”靶點正在被重新定義 | Bilingual

編者按：超過85%的致病蛋白因其在結構與功能上的限制，使傳統小分子與抗體療法難以奏效，長期被視為“不可成藥”。但隨著結構生物學、化學生物學以及新分子機制等領域的不斷突破，“不可成藥”的邊界正在被重新改寫。科學進展和新型治療模式正為此前難以觸及的關鍵蛋白打開全新的干預路徑。截至今年9月，已有超過10款靶向此類“不可成藥”靶點的新藥成功獲批上市，并帶動百余款候選藥物加速向前推進。在這一創新浪潮中，靶向蛋白降解（TPD）技術憑借“從源頭清除病理蛋白”的作用機制受到關注，也為傳統難以成藥的靶點帶來了治療的機會。面對TPD中蛋白降解靶向嵌合體（PROTAC?）等結構復雜、機制新穎的分子類型，藥明康德早在TPD技術興起之初便前瞻性布局，圍繞TPD開發構建起一體化賦能平臺，助力全球合作伙伴高效推進PROTAC?藥物從早期發現邁向臨床試驗階段。本文將介紹“不可成藥”背后的科學難點，并展示包括靶向蛋白降解在內的前沿技術如何加速將“不可能”變為“可能”。

在生命科學領域，“不可成藥”（undruggable）蛋白指那些難以通過傳統藥物方式進行調控的關鍵靶點。這類蛋白通常在維持細胞命運、調控信號通路或驅動疾病進展中發揮核心作用，但卻因其獨特的結構或功能特征，難以被小分子藥物或抗體精準結合。從機制來看，導致蛋白“不可成藥”的主要原因包括以下幾方面。

首先，一些蛋白缺乏明顯的結合口袋。例如小三磷酸鳥苷水解酶（GTPases）中的RAS家族成員（KRAS、HRAS與NRAS），由于其表面缺乏可靶向的結合位點，長期以來被視為典型的不可成藥靶點。當蛋白主要依賴蛋白-蛋白相互作用（PPI）發揮功能時，情況同樣復雜——部分轉錄因子（TFs）與表觀遺傳靶點的PPI界面通常較大、較淺或結構不明確，使得常規小分子難以有效結合，其中Bcl-2家族的抗凋亡蛋白便是代表性例子。與此相似的是具有高度動態結構、能夠與多種蛋白相互作用的內在無序蛋白（IDPs），由于缺乏穩定的結合界面，也屬于難以成藥的類別。此外，在調節細胞動態中發揮重要作用的磷酸酶（phosphatases），因家族內部結構高度相似，容易導致藥物選擇性不足與較高的副作用風險，同樣阻礙了相關藥物發現的進展。

除了結構因素外，蛋白的功能屬性及其細胞內定位同樣深刻影響其成藥性。許多表觀遺傳靶點和轉錄因子不僅是致病機制中的關鍵節點，在正常細胞中也承擔著重要生理功能，這使得靶向此類蛋白的藥物更容易引發毒性風險。同時，由于它們多位于細胞核內，也顯著增加了藥物遞送的難度——一旦藥物無法在細胞核中達到足夠的有效濃度，其療效往往難以充分發揮。

圖片來源：123RF

在此背景下，如何高選擇性地靶向不可成藥靶點并克服耐藥性問題，被視為當前醫藥研發中既極具挑戰、又極具潛力的前沿方向。以轉錄因子為例，它們在腫瘤和神經退行性疾病領域尤其備受關注。值得重點關注的核心轉錄因子包括參與腫瘤發生過程的p53、Myc、雌激素受體（ER）、雄激素受體（AR）；與衰老及神經退行性疾病相關的XBP1、NRF2；以及在免疫性疾病中發揮重要作用的NF-κB、BTB、BACH等。

然而，隨著科技進步，許多曾被視為“不可成藥”的靶點正被逐步攻克，一系列新型藥物分子相繼涌現，包括PROTAC?、分子膠、多肽以及復雜的大環化合物等，為難以成藥領域帶來突破。截至目前，已有超過10種針對先前被認為不可成藥靶點的新藥獲批上市，而處于臨床試驗階段的候選藥物更是多達數百種，推動了全球早期研究項目的持續增長。

今年8月，美國FDA已受理為PROTAC?療法vepdegestrant遞交的新藥申請（NDA），用于治療既往接受過內分泌治療、雌激素受體陽性（ER+）/人表皮生長因子受體2陰性（HER2-）且伴有ESR1突變的晚期或轉移性乳腺癌患者。根據新聞稿，vepdegestrant是首個在乳腺癌患者中展現臨床獲益的PROTAC?療法。若獲批，該藥物將成為首個獲美國FDA批準的PROTAC?雌激素受體降解劑。

在眾多創新策略中，靶向蛋白降解近年來備受關注。以PROTAC?為代表的新型分子不再通過抑制蛋白功能來實現作用，而是通過招募E3泛素連接酶，將目標蛋白（POI）標記并引導至蛋白酶體降解，從源頭上切斷病理機制。由于PROTAC?分子無需與POI的特定活性位點結合即可觸發降解，對傳統難以成藥的靶點（如轉錄因子）提供了全新的干預可能。同時，PROTAC?分子在完成降解后還能循環利用，這也有望增強藥效、降低劑量需求，從而提升治療的安全窗口。

在靶向蛋白降解療法約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。

截至今年年中，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。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。

面向未來，科學家面對“不可成藥”靶點已不再束手無策。如今，這些曾經阻礙藥物發現的難題，反而成為激發創新的起點。隨著結構生物學、化學生物學與新一代蛋白降解技術的不斷融合，越來越多曾經被視為“不可成藥”的蛋白正被一個個攻克。依托端到端的一體化CRDMO賦能平臺，藥明康德致力于加速客戶開發突破性療法，幫助合作伙伴將創新成果高效轉化為造福全球患者的解決方案，以踐行“讓天下沒有難做的藥，難治的病”的愿景。

Redefining the “Undruggable”: A New Era in Precision Medicine

More than 85% of disease-associated proteins have long been considered “undruggable” because their structural and functional features limit the effectiveness of traditional small-molecule and antibody therapies. Today, breakthroughs in structural biology, chemical biology, and new modality mechanisms are redrawing the “undruggable” boundary: scientific advances and emerging treatment strategies are opening new intervention paths for previously unreachable targets, driving the approval of over 10 medicines against such “undruggable” proteins and propelling hundreds of additional candidates through development. Within this innovation wave, targeted protein degradation (TPD) has stood out for its ability to “eliminate disease-causing proteins at the source,” creating new opportunities for historically difficult proteins. WuXi AppTec invested early in TPD and built a fully integrated enabling platform around modalities such as PROTAC? degraders, helping global partners efficiently advance their programs from early discovery into clinical trials. This article examines the scientific challenges behind “undruggable” targets and highlights how cutting-edge technologies such as TPD are accelerating breakthroughs in reaching these challenging targets.

In the life sciences field, “undruggable” proteins refer to critical disease-driving targets that remain difficult to modulate using traditional therapeutic approaches. These proteins often play essential roles in maintaining cell fate, regulating signaling pathways, or driving disease progression. Yet their unique structural or functional characteristics make them challenging for small molecules or antibodies to bind with high selectivity. Mechanistically, several factors contribute to why certain proteins are considered “undruggable.”

First, some proteins lack well-defined binding pockets.A classic example is the RAS family of small GTPases—KRAS, HRAS, and NRAS—which for decades were deemed undruggable because their protein surfaces offer no obvious druggable sites. For proteins that function primarily through protein–protein interactions (PPIs), the challenge is equally significant: many transcription factors (TFs) and epigenetic regulators feature large, shallow, or structurally ambiguous PPI interfaces that are not easily accessible to conventional small-molecule engagement. Anti-apoptotic members of the Bcl-2 family exemplify this difficulty. Similarly, intrinsically disordered proteins (IDPs), characterized by highly dynamic structures and the ability to interact with multiple partners, lack stable binding interfaces and are therefore difficult to drug. In addition, phosphatases—key regulators of cellular signaling—pose their own challenge:their highly conserved active sites often lead to poor selectivity and higher safety risks, hampering drug discovery progress.

Beyond structural constraints, a protein’s functional attributes and cellular localization also shape its druggability.Many epigenetic targets and transcription factors are not only central to disease mechanisms but also indispensable for normal cellular function, increasing the likelihood of toxicity when inhibited.Compounding this complexity, these proteins are predominantly located in the nucleus, creating significant barriers for drug delivery—if a therapy cannot achieve sufficient nuclear concentration, it cannot exert its intended pharmacological effect.

Source: 123RF

Against this backdrop, achieving highly selective targeting of undruggable proteins while overcoming drug resistance has emerged as both a major challenge and a high-potential frontier in pharmaceutical R&D. Transcription factors, for example, have drawn particular attention in oncology and neurodegenerative diseases. Key transcription factors of interest include p53, Myc, estrogen receptor (ER), and androgen receptor (AR) involved in tumorigenesis; XBP1 and NRF2 associated with aging and neurodegenerative disorders; as well as NF-κB, BTB, and BACH, which play critical roles in immune-related diseases.

However, rapid advances in science and technology are redefining what is possible. Many targets once viewed as undruggable are now being unlocked, driven by the emergence of new therapeutic modalities—including PROTACs (proteolysis-targeting chimeras), molecular glues, peptides, and complex macrocycles.To date, more than 10 medicines aimed at previously undruggable targets have been approved, and hundreds more are advancing through clinical development.

In August of this year, the U.S. FDA has accepted the New Drug Application (NDA) for the PROTAC? therapy vepdegestrant, intended for patients with previously treated estrogen receptor-positive (ER+)/HER2-negative metastatic or advanced breast cancer harboring ESR1 mutations. According to the announcement, vepdegestrant is the first PROTAC? therapy to demonstrate clinical benefit in breast cancer patients.If approved, it will become the first FDA-approved PROTAC? estrogen receptor degrader.

Among these breakthrough strategies, TPD has gained significant traction. Rather than inhibiting protein function, innovative modalities such as PROTAC? molecules recruit E3 ubiquitin ligases to tag and direct disease-driving proteins (POIs) to the proteasome for degradation—shutting down pathogenic pathways at the source. Since PROTAC? molecules do not require binding to a traditional active site, they unlock intervention opportunities for historically difficult targets such as transcription factors. Moreover, because PROTAC? molecules can be catalytically recycled after inducing degradation, they may boost therapeutic potency, reduce dosing requirements, and potentially improve safety.

Over nearly a decade of targeted protein degradation development in the industry, WuXi AppTec has been deeply involved at every step, providing partners with fully integrated end-to-end support. Even in the early days of PROTAC? research, WuXi AppTec proactively invested in relevant capabilities, establishing a comprehensive platform that spans discovery, synthesis, purification, and testing.As new generations of TPD technologies continue to emerge, the company has rapidly expanded its capabilities, now covering PROTAC?, molecular glues, AUTAC, LYTAC, DUBTAC, RIBOTAC, PHICS, DAC, and other leading modalities.

To date, WuXi AppTec has collaborated with more than 150 companies around the world across all stages of TPD compound development. Over the years, WuXi AppTec has synthesized more than 188,000 complex TPD molecules, with over 70 advancing into preclinical candidate selection and more than 10 now in late-stage development.

Looking ahead, scientists are no longer constrained by so-called “undruggable” targets. What was once considered a barrier to innovation has now become a powerful starting point for breakthroughs. As structural biology, chemical biology, and next-generation protein degradation technologies converge, more and more once-intractable targets are becoming therapeutically accessible.

WuXi AppTec will continue leveraging its integrated, end-to-end CRDMO platform to unlock new possibilities and bring transformative therapies to patients worldwide—fulfilling the vision of “every drug can be made and every disease can be treated.”

參考資料：

[1] Xie X, Yu T, Li X, Zhang N, Foster LJ, Peng C, Huang W, He G. Recent advances in targeting the "undruggable" proteins: from drug discovery to clinical trials. Signal Transduct Target Ther. 2023 Sep 6;8(1):335. doi: 10.1038/s41392-023-01589-z. PMID: 37669923; PMCID: PMC10480221.

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