編者按：誘導(dǎo)接近（induced proximity）機(jī)制通過將蛋白或核酸拉近形成復(fù)合體，從而調(diào)控靶點(diǎn)功能?；谶@一機(jī)制開發(fā)的靶向蛋白降解劑（TPD）已成為新藥研發(fā)的熱點(diǎn)之一。與傳統(tǒng)抑制劑不同，它們無需直接抑制靶蛋白活性，而是通過降解疾病相關(guān)蛋白，有望靶向許多長(zhǎng)期被認(rèn)為“不可成藥”的靶點(diǎn)。藥明康德在TPD技術(shù)剛剛起步時(shí)，就開始布局相關(guān)能力和技術(shù)，積累了豐富的成功經(jīng)驗(yàn)，搭建起集發(fā)現(xiàn)、合成、分析純化和測(cè)試等能力于一體的一站式賦能平臺(tái)。近年來，基于誘導(dǎo)接近機(jī)制的研發(fā)已不再局限于TPD，還擴(kuò)展至針對(duì)難以成藥靶點(diǎn)的抑制劑開發(fā)，以及組織特異性藥物的開發(fā)。本文將回顧2025年該領(lǐng)域的最新進(jìn)展，并介紹藥明康德的一體化CRDMO平臺(tái)如何高效解決誘導(dǎo)接近藥物開發(fā)過程中的諸多挑戰(zhàn)。

異雙功能性蛋白降解劑：首款PROTAC?療法有望獲批，降解靶點(diǎn)多元化

異雙功能性蛋白降解劑的一端與靶點(diǎn)蛋白結(jié)合，而另一端與介導(dǎo)蛋白酶體降解、溶酶體降解、或細(xì)胞內(nèi)吞等蛋白降解過程的功能性蛋白相結(jié)合，從而促進(jìn)對(duì)靶點(diǎn)蛋白的選擇性降解。其中臨床進(jìn)展最快的是蛋白降解靶向嵌合體（PROTAC?）。今年8月，美國(guó)FDA接受靶向降解雌激素受體（ER）的vepdegestrant的新藥申請(qǐng)（NDA），用于治療既往接受過內(nèi)分泌治療、ER+/HER2-且伴有ESR1突變的晚期或轉(zhuǎn)移性乳腺癌患者。如果最終獲批，它將成為首個(gè)獲FDA批準(zhǔn)的PROTAC?雌激素受體降解劑。這也標(biāo)志著在PROTAC?概念誕生的20多年后，這類創(chuàng)新療法將進(jìn)入全新階段。

Vepdegestrant之外，多款異雙功能性蛋白降解劑也獲得積極臨床進(jìn)展，例如Arvinas公司靶向LRRK2的PROTAC?分子ARV-102在1期臨床試驗(yàn)中顯著降低健康志愿者中樞神經(jīng)系統(tǒng)（CNS）和外周的LRRK2蛋白水平。其靶向BCL6的PROTAC?分子ARV-393在首次人體臨床試驗(yàn)中也觀察到多名非霍奇金淋巴瘤（NHL）患者產(chǎn)生應(yīng)答。

值得一提的是，除了已有獲批藥物所靶向的成熟靶點(diǎn)（例如ER、AR、BTK、EGFR、IKZF等）之外，新一代異雙功能性蛋白降解劑的靶點(diǎn)類型更為豐富，其中包括多個(gè)傳統(tǒng)小分子藥物難以靶向的靶點(diǎn)，例如STAT6、BCL6、IRF5等轉(zhuǎn)錄因子，以及IRAK4、KRAS G12D等難以成藥的靶點(diǎn)。治療疾病的范圍也從腫瘤學(xué)適應(yīng)癥擴(kuò)展至神經(jīng)退行性疾病和免疫介導(dǎo)疾病。這一趨勢(shì)顯示出靶向降解療法在攻克難以成藥靶點(diǎn)方面的潛力。

異雙功能性蛋白降解劑并不只局限于降解細(xì)胞內(nèi)蛋白。Biohaven公司開發(fā)的靶向蛋白降解劑BHV-1300和BHV-1400在早期臨床試驗(yàn)中表現(xiàn)出顯著降低細(xì)胞外蛋白水平的能力。這兩款在研藥物均為雙特異性分子，一端與靶蛋白結(jié)合，另一端與肝細(xì)胞表面的去唾液酸糖蛋白受體（ASGPR）結(jié)合。該受體可介導(dǎo)肝細(xì)胞通過內(nèi)吞作用，將靶蛋白攝入細(xì)胞內(nèi)并降解。臨床試驗(yàn)數(shù)據(jù)顯示，BHV-1300和BHV-1400注射入患者體內(nèi)后，短短數(shù)小時(shí)內(nèi)即介導(dǎo)了靶蛋白的快速降解，蛋白水平降幅達(dá)到70%-80%，凸顯出這類藥物迅速的起效速度與臨床應(yīng)用潛力。

分子膠降解劑：多款療法獲得臨床概念驗(yàn)證，大藥企持續(xù)布局

分子膠降解劑通過與靶蛋白或E3泛素連接酶結(jié)合，即可誘導(dǎo)或穩(wěn)定它們之間的相互作用，從而實(shí)現(xiàn)蛋白降解。這一細(xì)分領(lǐng)域近年來得到多家大藥企的青睞。在2025年，多款在研分子膠降解劑獲得積極臨床結(jié)果。例如，在近期結(jié)束的美國(guó)血液學(xué)會(huì)（ASH）年會(huì)上，百時(shí)美施貴寶（Bristol Myers Squibb）公布了在研口服E3泛素連接酶cereblon調(diào)節(jié)藥物（CELMoD）mezigdomide和iberdomide在多發(fā)性骨髓瘤患者中的更新臨床研究結(jié)果，以及golcadomide在NHL患者中的研究進(jìn)展。

Monte Rosa Therapeutics公司靶向降解GSPT1的分子膠降解劑MRT-2359，在治療對(duì)雄激素受體（AR）靶向療法耐藥的去勢(shì)抵抗性前列腺癌（CRPC）患者時(shí)表現(xiàn)出抗癌活性。此外，其靶向VAV1的分子膠降解劑MRT-6160，在健康志愿者中進(jìn)行的1期臨床試驗(yàn)中表現(xiàn)出良好的安全性和耐受性，并且可將外周血T細(xì)胞中的VAV1水平降低超過90%。

該公司在今年9月還與諾華（Novartis）達(dá)成新的研發(fā)協(xié)議，聯(lián)合推動(dòng)針對(duì)免疫介導(dǎo)疾病的創(chuàng)新分子膠降解劑的開發(fā)。

諾華與Monte Rosa Therapeutics公司的合作之外，多家大藥企也在分子膠領(lǐng)域持續(xù)布局。例如，今年6月，吉利德科學(xué)（Gilead Sciences）與Kymera Therapeutics公司達(dá)成研發(fā)授權(quán)與許可合作，共同開發(fā)靶向CDK2的分子膠降解劑。此外，艾伯維（AbbVie）公司在1月也與Neomorph公司達(dá)成超16億美元的分子膠蛋白降解劑研發(fā)合作。

一體化平臺(tái)助力分子膠早期發(fā)現(xiàn)

藥明康德一體化平臺(tái)的能力不但涵蓋PROTAC?，還包括分子膠、以及多種新興雙功能分子。以分子膠藥物發(fā)現(xiàn)為例，早期研發(fā)階段中，無偏倚藥物篩選的低命中率始終是一大挑戰(zhàn)。為助力合作伙伴有效應(yīng)對(duì)這一難題，藥明康德采取了“雙軌并進(jìn)”的策略，構(gòu)建起一套兼顧廣度與深度的化合物庫(kù)體系：一方面，通過多樣化的DNA編碼化合物庫(kù)（DEL）大范圍探索新靶點(diǎn)；另一方面，借助聚焦化合物庫(kù)精細(xì)化研究已知蛋白體系，提升發(fā)現(xiàn)效率。

▲藥明康德分子膠發(fā)現(xiàn)平臺(tái)

在分子膠藥物的早期發(fā)現(xiàn)過程中，藥明康德不僅依賴DNA編碼化合物庫(kù)進(jìn)行篩選，還不斷引入并整合多種先進(jìn)技術(shù)，以助力合作伙伴拓展分子膠藥物的發(fā)現(xiàn)能力。其中，親和篩選質(zhì)譜（ASMS）提供無標(biāo)記篩選手段。藥明康德構(gòu)建了一個(gè)涵蓋超過37萬個(gè)小分子的廣譜化合物庫(kù)，通過比較這些分子在單蛋白與雙蛋白條件下的質(zhì)譜信號(hào)差異，精準(zhǔn)識(shí)別出能夠促進(jìn)蛋白–蛋白相互作用的潛在分子膠候選物，從而識(shí)別出潛在促互作的小分子。

與此同時(shí)，公司還部署高通量篩選（HTS）技術(shù)。在“一孔一化合物”的自動(dòng)化運(yùn)行模式下，結(jié)合蛋白結(jié)合能力或降解能力等功能性實(shí)驗(yàn)，HTS能迅速鎖定具備生物活性的候選分子，大幅提升篩選效率與準(zhǔn)確性。通過將ASMS與HTS等多維篩選工具與DEL平臺(tái)深度融合，藥明康德打破了單一篩選方式的限制，讓更多不同類型的靶點(diǎn)進(jìn)入分子膠研究視野，進(jìn)一步拓寬了分子膠在多類靶點(diǎn)上的研發(fā)空間。

超越蛋白降解，創(chuàng)新誘導(dǎo)接近藥物獲得概念驗(yàn)證

選擇性降解目標(biāo)蛋白只是誘導(dǎo)接近作用機(jī)制的應(yīng)用之一，近年來多家公司已經(jīng)著手利用誘導(dǎo)接近機(jī)制，開辟調(diào)控信號(hào)通路新方法。例如，Revolution Medicines公司研發(fā)的RAS抑制劑elironrasib通過招募cyclophilin這一呈遞蛋白，實(shí)現(xiàn)了對(duì)激活狀態(tài)下KRAS G12C蛋白的特異性靶向與抑制。今年7月，該藥物獲得FDA授予的突破性療法認(rèn)定，用于治療攜帶

KRAS

Halda Therapeutics公司的調(diào)節(jié)誘導(dǎo)接近靶向嵌合體（RIPTAC）則代表另一種新策略。這類異雙功能分子的一端結(jié)合富集于癌細(xì)胞中的靶點(diǎn)蛋白，另一端結(jié)合細(xì)胞生存必需的關(guān)鍵蛋白。當(dāng)細(xì)胞同時(shí)表達(dá)這兩種蛋白時(shí)，RIPTAC分子將兩者結(jié)合形成復(fù)合體，使關(guān)鍵蛋白失活，從而誘導(dǎo)癌細(xì)胞死亡。今年公布的首個(gè)臨床試驗(yàn)結(jié)果顯示，該公司靶向雄激素受體的RIPTAC在研藥物HLD-0915，在1/2期臨床試驗(yàn)中表現(xiàn)出令人鼓舞的抗腫瘤活性跡象，包括前列腺特異性抗原（PSA）水平下降及依據(jù)實(shí)體瘤療效評(píng)估標(biāo)準(zhǔn)（RECIST）觀察到的緩解。在今年11月，強(qiáng)生（Johnson & Johnson）宣布，將以總額30.5億美元收購(gòu)Halda Therapeutics。

值得一提的是，作為全球支持蛋白降解療法研發(fā)的重要賦能平臺(tái)之一，藥明康德也一路見證了Halda公司從萌芽、成長(zhǎng)，到如今的快速發(fā)展。在2024年藥明康德舉辦的投資者日期間，藥明康德聯(lián)席首席執(zhí)行官楊青博士提到了這些成就背后的創(chuàng)業(yè)和合作故事。公開信息顯示，早在2016年，藥明康德在蛋白降解療法開發(fā)尚在起步階段時(shí)就建設(shè)了相應(yīng)能力，也是全球最早賦能RIPTAC類藥物研發(fā)的公司之一。作為Halda的合作伙伴，藥明康德在多個(gè)環(huán)節(jié)深度賦能該公司的新藥研發(fā)，助力一流基礎(chǔ)科學(xué)發(fā)現(xiàn)轉(zhuǎn)化為創(chuàng)新療法。

強(qiáng)生公司之外，多家大藥企也在布局非降解型誘導(dǎo)接近療法。例如今年2月，禮來（Eli Lilly and Company）與Magnet Biomedicine公司簽署一項(xiàng)近13億美元的合作協(xié)議。雙方合作的范圍不僅涵蓋基于分子膠的蛋白降解劑研發(fā)，還將探索利用分子膠促進(jìn)蛋白質(zhì)之間產(chǎn)生誘導(dǎo)接近和協(xié)同作用，精準(zhǔn)靶向疾病相關(guān)組織的創(chuàng)新作用機(jī)制。

今年5月，基因泰克（Genentech）與Orionis Biosciences達(dá)成超過20億美元的研發(fā)合作協(xié)議，致力于開發(fā)靶向難以成藥靶點(diǎn)的小分子單價(jià)分子膠藥物，用于癌癥治療。

第一三共在今年11月與General Proximity達(dá)成研發(fā)合作，共同開發(fā)新一代基于誘導(dǎo)接近的抗癌藥物。

▲2025年大型藥企在誘導(dǎo)接近領(lǐng)域的布局（數(shù)據(jù)來源：公開資料，截至12月9日）

誘導(dǎo)接近領(lǐng)域的創(chuàng)新無處不在。藥明康德的核心策略之一是跟隨科學(xué)的發(fā)展。面對(duì)層出不窮的新分子類型，藥明康德及時(shí)捕捉機(jī)遇，為立足前沿的創(chuàng)新者賦能。今年9月的藥明康德投資者開放日上發(fā)布的數(shù)據(jù)顯示，在靶向蛋白降解領(lǐng)域，藥明康德R端業(yè)務(wù)客戶滲透率高達(dá)67%。

展望未來，藥明康德將繼續(xù)秉持“讓天下沒有難做的藥，難治的病”的愿景，依托全球研發(fā)基地與生產(chǎn)網(wǎng)絡(luò)，以獨(dú)特的一體化、端到端的CRDMO模式，助力包括靶向蛋白降解劑在內(nèi)的誘導(dǎo)接近藥物的開發(fā)，幫助合作伙伴將科學(xué)創(chuàng)新轉(zhuǎn)化為惠及全球患者的變革性藥物。

CRDMO: 2025 Review of Induced Proximity Drugs

The induced proximity mechanism regulates target function by bringing proteins or nucleic acids into close proximity to form complexes. Targeted protein degraders (TPDs) developed on this basis have become one of the hottest areas in drug discovery. Unlike traditional inhibitors, TPDs do not need to block target activity directly; instead, they eliminate disease-related proteins, opening opportunities to tackle many proteins once deemed “undruggable.” When TPD technology was still in its infancy, WuXi AppTec started building relevant capabilities. Since then, the company has established a comprehensive, integrated platform encompassing discovery, synthesis, purification, analysis, and testing. In recent years, induced proximity has extended beyond TPDs to include inhibitors for hard-to-drug targets and tissue-specific therapies. This article reviews progress in 2025 and highlights how WuXi AppTec’s integrated CRDMO platform helps overcome the unique challenges of developing induced proximity medicines.

Bifunctional Degraders: First PROTAC? Therapy Expected to Receive Approval

Bifunctional degraders are designed so that one end binds the target protein, while the other recruits proteins involved in proteasomal degradation, lysosomal degradation, or endocytosis, enabling selective degradation. Among these, proteolysis-targeting chimeras (PROTAC?) have achieved the most advanced clinical progress.

A major milestone occurred in August when the U.S. FDA accepted the NDA for vepdegestrant, a PROTAC? targeting the estrogen receptor (ER) for previously treated ER+/HER2? metastatic or advanced breast cancer withESR1mutations.If approved, vepdegestrant would become the first FDA-approved PROTAC? estrogen receptor degrader, marking a new stage for a modality first conceptualized more than 20 years ago.

Additional bifunctional degraders are also advancing, including:

ARV-102, developed by Arvinas to target LRRK2, significantly reduced central nervous system (CNS) and peripheral protein levels in healthy volunteers in a Phase 1 trial.

ARV-393, targeting BCL6, demonstrated responses in several non-Hodgkin lymphoma (NHL) patients in a first-in-human evaluation.

These programs highlight a broader trend.Beyond well-validated targets such as ER, AR, BTK, EGFR, IKZF, next-generation degraders are reaching more diverse and historically difficult targets, including transcription factors such as STAT6, BCL6, IRF5, as well as challenging targets such as IRAK4 and KRAS G12D.

Development has also expanded from oncology to neurodegenerative and immune-mediated diseases, underscoring the therapeutic promise of targeted degradation.

Bifunctional degraders are not limited to intracellular proteins. Biohaven’s BHV-1300 and BHV-1400 demonstrated rapid reduction of extracellular proteins in early trials. These bispecific molecules bind both the target protein and the ASGPR receptor on hepatocytes, enabling endocytosis and degradation.

Within hours of administration, both agents reduced target protein levels by 70–80%, highlighting rapid onset and clear clinical potential.

Molecular Glue Degraders: Proof of Concept Across Multiple Programs as Big Pharma Invests Aggressively

Molecular glue degraders induce or stabilize interactions between target proteins and E3 ligases, enabling degradation. This space has attracted strong pharmaceutical interest, and 2025 brought a wave of positive clinical data.

At the ASH Annual Meeting, Bristol Myers Squibb presented updated results for mezigdomide and iberdomide, oral CELMoD agents in multiple myeloma; and new findings for golcadomide in NHL.

Monte Rosa Therapeutics reported that MRT-2359, targeting GSPT1, showed antitumor activity in CRPC that was resistant to AR-directed therapy. MRT-6160, targeting VAV1, reduced VAV1 levels in peripheral T cells by >90% with favorable safety in healthy volunteers.

In September, Monte Rosa and Novartis entered an R&D agreement to co-develop degraders for immune-mediated diseases.

Other partnerships demonstrate sustained momentum:

In June, Gilead Sciences and Kymera Therapeutics initiated a collaboration to develop a CDK2 molecular glue.

In January, AbbVie formed a >$1.6 billion partnership with Neomorph to advance protein degraders.

Together, these alliances illustrate strategic, long-term investment from leading biopharma companies.

WuXi AppTec’s integrated platform supports not only PROTAC? development but also molecular glues and other bifunctional modalities. By uniting cutting-edge screening technologies, tailored library design, and deep scientific expertise,WuXi AppTec offers a fully integrated platform for molecular glue discovery. This approach supports partners across:

? Hit identification and validation

? Mechanistic characterization and degradation profiling

? Lead optimization and SAR development

Beyond Degradation: New Induced Proximity Mechanisms Achieve Clinical Validation

Selective degradation represents only one application of induced proximity. Increasingly, new approaches are being developed to regulate signaling pathways.

A notable example comes from Revolution Medicines.Its RAS inhibitor elironrasib recruited cyclophilin as a presenter protein to selectively target and inhibit active-state KRAS G12C.In July, the FDA granted Breakthrough Therapy Designation for elironrasib in KRAS G12C-mutant NSCLC. Phase 1 data were compelling: in previously treated patients without prior KRAS inhibitors, monotherapy achieved a 56% ORR and 94% disease control rate (DCR). In combination with pembrolizumab as first-line therapy, the ORR reached 100%, signaling strong early potential.

Halda Therapeutics is advancing another strategy with Regulated Induced Proximity Targeting Chimeras (RIPTACs).These heterobifunctional molecules bind a cancer-enriched target protein on one end and an essential survival protein on the other. By bringing the two together, RIPTACs inactivate the survival protein, triggering cancer cell death.

Early clinical results for HLD-0915, a RIPTAC targeting androgen receptor, showed PSA reductions and RECIST-based responses.

In November, Johnson & Johnson announced a $3.05 billion acquisition of Halda Therapeutics.

Beyond J&J, additional big pharmaceutical companies are advancing non-degrader induced proximity approaches through collaborations:

In February, Eli Lilly signed a nearly $1.3 billion agreement with Magnet Biomedicine.

In May, Genentech and Orionis Biosciences launched a >$2 billion collaboration to develop monovalent glues for cancer.

In November, Daiichi Sankyo partnered with General Proximity on next-generation induced proximity anticancer drugs.

Together, these collaborations demonstrate expanding industrial commitment.

Looking Ahead

Innovation in induced proximity is unfolding across the entire biopharmaceutical landscape. One of WuXi AppTec’s core strategies is to follow where the science leads. As new molecular types and mechanisms continue to emerge, WuXi AppTec rapidly identifies opportunities and empowers innovators at the frontier.

During the 2025 WuXi AppTec Investor Day, data showed that in the targeted protein degradation space, 67% of active clients in the field collaborate with WuXi AppTec since 2021.

Guided by its vision that “every drug can be made and every disease can be treated”, WuXi AppTec remains committed to leveraging its unique, fully integrated, end-to-end CRDMO model to help partners transform scientific innovation into transformative therapies for patients worldwide.

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