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

編者按：超過(guò)85%的致病蛋白因其在結(jié)構(gòu)與功能上的限制，使傳統(tǒng)小分子與抗體療法難以奏效，長(zhǎng)期被視為“不可成藥”。但隨著結(jié)構(gòu)生物學(xué)、化學(xué)生物學(xué)以及新分子機(jī)制等領(lǐng)域的不斷突破，“不可成藥”的邊界正在被重新改寫(xiě)。科學(xué)進(jìn)展和新型治療模式正為此前難以觸及的關(guān)鍵蛋白打開(kāi)全新的干預(yù)路徑。截至今年9月，已有超過(guò)10款靶向此類(lèi)“不可成藥”靶點(diǎn)的新藥成功獲批上市，并帶動(dòng)百余款候選藥物加速向前推進(jìn)。在這一創(chuàng)新浪潮中，靶向蛋白降解（TPD）技術(shù)憑借“從源頭清除病理蛋白”的作用機(jī)制受到關(guān)注，也為傳統(tǒng)難以成藥的靶點(diǎn)帶來(lái)了治療的機(jī)會(huì)。面對(duì)TPD中蛋白降解靶向嵌合體（PROTAC?）等結(jié)構(gòu)復(fù)雜、機(jī)制新穎的分子類(lèi)型，藥明康德早在TPD技術(shù)興起之初便前瞻性布局，圍繞TPD開(kāi)發(fā)構(gòu)建起一體化賦能平臺(tái)，助力全球合作伙伴高效推進(jìn)PROTAC?藥物從早期發(fā)現(xiàn)邁向臨床試驗(yàn)階段。本文將介紹“不可成藥”背后的科學(xué)難點(diǎn)，并展示包括靶向蛋白降解在內(nèi)的前沿技術(shù)如何加速將“不可能”變?yōu)椤翱赡堋薄?/strong>

在生命科學(xué)領(lǐng)域，“不可成藥”（undruggable）蛋白指那些難以通過(guò)傳統(tǒng)藥物方式進(jìn)行調(diào)控的關(guān)鍵靶點(diǎn)。這類(lèi)蛋白通常在維持細(xì)胞命運(yùn)、調(diào)控信號(hào)通路或驅(qū)動(dòng)疾病進(jìn)展中發(fā)揮核心作用，但卻因其獨(dú)特的結(jié)構(gòu)或功能特征，難以被小分子藥物或抗體精準(zhǔn)結(jié)合。從機(jī)制來(lái)看，導(dǎo)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(jié)合口袋。例如小三磷酸鳥(niǎo)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(jié)合位點(diǎn)，長(zhǎng)期以來(lái)被視為典型的不可成藥靶點(diǎn)。當(dāng)?shù)鞍字饕蕾?lài)蛋白-蛋白相互作用（PPI）發(fā)揮功能時(shí)，情況同樣復(fù)雜——部分轉(zhuǎn)錄因子（TFs）與表觀遺傳靶點(diǎn)的PPI界面通常較大、較淺或結(jié)構(gòu)不明確，使得常規(guī)小分子難以有效結(jié)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(dòng)態(tài)結(jié)構(gòu)、能夠與多種蛋白相互作用的內(nèi)在無(wú)序蛋白（IDPs），由于缺乏穩(wěn)定的結(jié)合界面，也屬于難以成藥的類(lèi)別。此外，在調(diào)節(jié)細(xì)胞動(dòng)態(tài)中發(fā)揮重要作用的磷酸酶（phosphatases），因家族內(nèi)部結(jié)構(gòu)高度相似，容易導(dǎo)致藥物選擇性不足與較高的副作用風(fēng)險(xiǎn)，同樣阻礙了相關(guān)藥物發(fā)現(xiàn)的進(jìn)展。

除了結(jié)構(gòu)因素外，蛋白的功能屬性及其細(xì)胞內(nèi)定位同樣深刻影響其成藥性。許多表觀遺傳靶點(diǎn)和轉(zhuǎn)錄因子不僅是致病機(jī)制中的關(guān)鍵節(jié)點(diǎn)，在正常細(xì)胞中也承擔(dān)著重要生理功能，這使得靶向此類(lèi)蛋白的藥物更容易引發(fā)毒性風(fēng)險(xiǎn)。同時(shí)，由于它們多位于細(xì)胞核內(nèi)，也顯著增加了藥物遞送的難度——一旦藥物無(wú)法在細(xì)胞核中達(dá)到足夠的有效濃度，其療效往往難以充分發(fā)揮。

圖片來(lái)源：123RF

在此背景下，如何高選擇性地靶向不可成藥靶點(diǎn)并克服耐藥性問(wèn)題，被視為當(dāng)前醫(yī)藥研發(fā)中既極具挑戰(zhàn)、又極具潛力的前沿方向。以轉(zhuǎn)錄因子為例，它們?cè)谀[瘤和神經(jīng)退行性疾病領(lǐng)域尤其備受關(guān)注。值得重點(diǎn)關(guān)注的核心轉(zhuǎn)錄因子包括參與腫瘤發(fā)生過(guò)程的p53、Myc、雌激素受體（ER）、雄激素受體（AR）；與衰老及神經(jīng)退行性疾病相關(guān)的XBP1、NRF2；以及在免疫性疾病中發(fā)揮重要作用的NF-κB、BTB、BACH等。

然而，隨著科技進(jìn)步，許多曾被視為“不可成藥”的靶點(diǎn)正被逐步攻克，一系列新型藥物分子相繼涌現(xiàn)，包括PROTAC?、分子膠、多肽以及復(fù)雜的大環(huán)化合物等，為難以成藥領(lǐng)域帶來(lái)突破。截至目前，已有超過(guò)10種針對(duì)先前被認(rèn)為不可成藥靶點(diǎn)的新藥獲批上市，而處于臨床試驗(yàn)階段的候選藥物更是多達(dá)數(shù)百種，推動(dòng)了全球早期研究項(xiàng)目的持續(xù)增長(zhǎng)。

今年8月，美國(guó)FDA已受理為PROTAC?療法vepdegestrant遞交的新藥申請(qǐng)（NDA），用于治療既往接受過(guò)內(nèi)分泌治療、雌激素受體陽(yáng)性（ER+）/人表皮生長(zhǎng)因子受體2陰性（HER2-）且伴有ESR1突變的晚期或轉(zhuǎn)移性乳腺癌患者。根據(jù)新聞稿，vepdegestrant是首個(gè)在乳腺癌患者中展現(xiàn)臨床獲益的PROTAC?療法。若獲批，該藥物將成為首個(gè)獲美國(guó)FDA批準(zhǔn)的PROTAC?雌激素受體降解劑。

在眾多創(chuàng)新策略中，靶向蛋白降解近年來(lái)備受關(guān)注。以PROTAC?為代表的新型分子不再通過(guò)抑制蛋白功能來(lái)實(shí)現(xiàn)作用，而是通過(guò)招募E3泛素連接酶，將目標(biāo)蛋白（POI）標(biāo)記并引導(dǎo)至蛋白酶體降解，從源頭上切斷病理機(jī)制。由于PROTAC?分子無(wú)需與POI的特定活性位點(diǎn)結(jié)合即可觸發(fā)降解，對(duì)傳統(tǒng)難以成藥的靶點(diǎn)（如轉(zhuǎn)錄因子）提供了全新的干預(yù)可能。同時(shí)，PROTAC?分子在完成降解后還能循環(huán)利用，這也有望增強(qiáng)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(chǎn)業(yè)轉(zhuǎn)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(shí)，藥明康德就前瞻性地布局了相關(guān)能力和技術(shù)，搭建了集發(fā)現(xiàn)、合成、分析純化和測(cè)試等能力于一體的一體化賦能平臺(tái)，助力全球合作伙伴高效推進(jìn)藥物從早期發(fā)現(xiàn)到臨床試驗(yàn)階段。伴隨著新型靶向蛋白降解技術(shù)的持續(xù)涌現(xiàn)，藥明康德緊跟科學(xué)前沿，迅速構(gòu)建相關(guān)技術(shù)平臺(tái)，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(lèi)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(kāi)發(fā)的各個(gè)階段開(kāi)展合作。在賦能全球客戶(hù)的過(guò)程中，藥明康德已合成了超過(guò)18.8萬(wàn)種復(fù)雜的靶向蛋白降解化合物，其中70多種已進(jìn)入臨床前候選藥物階段，10多種已進(jìn)入后期開(kāi)發(fā)階段。

面向未來(lái)，科學(xué)家面對(duì)“不可成藥”靶點(diǎn)已不再束手無(wú)策。如今，這些曾經(jīng)阻礙藥物發(fā)現(xiàn)的難題，反而成為激發(fā)創(chuàng)新的起點(diǎn)。隨著結(jié)構(gòu)生物學(xué)、化學(xué)生物學(xué)與新一代蛋白降解技術(shù)的不斷融合，越來(lái)越多曾經(jīng)被視為“不可成藥”的蛋白正被一個(gè)個(gè)攻克。依托端到端的一體化CRDMO賦能平臺(tái)，藥明康德致力于加速客戶(hù)開(kāi)發(fā)突破性療法，幫助合作伙伴將創(chuàng)新成果高效轉(zhuǎn)化為造福全球患者的解決方案，以踐行“讓天下沒(méi)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.

免責(zé)聲明：本文僅作信息交流之目的，文中觀點(diǎn)不代表藥明康德立場(chǎng)，亦不代表藥明康德支持或反對(duì)文中觀點(diǎn)。本文也不是治療方案推薦。如需獲得治療方案指導(dǎo)，請(qǐng)前往正規(guī)醫(yī)院就診。

版權(quán)說(shuō)明：歡迎個(gè)人轉(zhuǎn)發(fā)至朋友圈，謝絕媒體或機(jī)構(gòu)未經(jīng)授權(quán)以任何形式轉(zhuǎn)載至其他平臺(tái)。轉(zhuǎn)載授權(quán)請(qǐng)?jiān)凇杆幟骺档隆刮⑿殴娞?hào)回復(fù)“轉(zhuǎn)載”，獲取轉(zhuǎn)載須知。