同行致遠 | 抗癌分子膠疾病控制率超90%；PROTAC?沖刺全球首批 | Bilingual

編者按：誘導接近（induced proximity）機制通過將蛋白或核酸拉近形成復合體，從而調控靶點功能。基于這一機制開發的靶向蛋白降解劑（TPD）已成為新藥研發的熱點之一。與傳統抑制劑不同，它們無需直接抑制靶蛋白活性，而是通過降解疾病相關蛋白，有望靶向許多長期被認為“不可成藥”的靶點。藥明康德在TPD技術剛剛起步時，就開始布局相關能力和技術，積累了豐富的成功經驗，搭建起集發現、合成、分析純化和測試等能力于一體的一站式賦能平臺。目前，該平臺已成功支持超過120款TPD分子的開發，其中20余款順利推進至臨床階段。近年來，基于誘導接近機制的研發已不再局限于TPD，還擴展至針對難以成藥靶點的抑制劑開發，以及組織特異性藥物的開發。本文將回顧2025年第三季度該領域的最新進展，并介紹藥明康德的一體化CRDMO平臺如何高效解決誘導接近藥物開發過程中的諸多挑戰。

靶向蛋白降解：FDA受理PROTAC?療法新藥申請

Arvinas與輝瑞（Pfizer）宣布，美國FDA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。

除了Arvinas公司，C4 Therapeutics公司還公布了靶向IKZF1/3的在研蛋白降解療法cemsidomide治療多發性骨髓瘤患者的1期臨床試驗結果。截至2025年7月23日，75 μg劑量組的客觀緩解率（ORR）為40%，100 μg劑量組的ORR為50%。該公司計劃在2026年初啟動注冊性臨床試驗。

Monte Rosa Therapeutics公司開發的靶向NEK7的分子膠蛋白降解劑MRT-8102，在1期臨床試驗中已完成首例患者給藥。這款口服選擇性分子膠降解劑有望用于治療與NLRP3、IL-1β和IL-6失調相關的炎癥性疾病。值得注意的是，該公司還在《科學》雜志發表論文，詳細介紹了其自主開發的人工智能（AI）和機器學習（ML）引擎如何發現可通過CRBN介導降解的人體蛋白，涵蓋多種不同的蛋白結構域與類別。這一突破顯著拓展了分子膠蛋白降解藥物的可操作靶點空間。該公司還在9月15日宣布與諾華（Novartis）達成57億美元的，攜手推動針對免疫介導疾病的創新降解劑研發。

TPD藥物雖具廣闊前景，但其開發也面臨獨特挑戰。例如，PROTAC?分子由于分子量大、結構復雜，通常存在溶解度差和藥代動力學性質不佳的問題。以下案例展示了藥明康德旗下合全藥業（WuXi STA）如何與合作伙伴攜手，有效應對這些挑戰。

解決TPD藥物開發痛點，加速創新療法進入臨床試驗

幾年前，一家公司因PROTAC?分子的生產難題，選擇與合全藥業合作，希望在14個月內完成候選藥物的生產，以支持IND申請及首次人體臨床試驗。然而，該候選分子的初始合成路線非常復雜，需要多達24個步驟，且最終產率僅為0.3%。此外，PROTAC?特定的分子結構進一步增加了產品結晶和純化難度。

同時，由于候選化合物分子量較大且水溶性低，其口服生物利用度只有0.9%。值得注意的是，在合成過程中還有三步涉及使用罕見金屬鈀（Pd）作為催化劑，這不僅帶來潛在安全隱患，更顯著提高了生產成本。

針對上述問題，合全藥業的工藝研發、生物催化及結晶工藝等團隊協同攻關，重新設計了一條合成路線，將合成步驟從原來的24步縮減至16步，并在其中兩個步驟中用生物催化劑替代了鈀催化劑。為攻克結晶難題，團隊采用高通量結晶篩選技術，迅速確定了符合純度與產量要求的結晶工藝，并通過優化大幅提升了生產過程的總產率。這些改進不但極大提高了整體合成工藝的可放大性，也提升了合成效率并降低了成本。

與此同時，合全藥業的制劑研發團隊針對藥物口服生物利用度低的問題，進行了全面的生物利用度增強技術篩選，最終選定噴霧干燥制備固體分散體（SDD）技術進行制劑制備。這種技術將難溶藥物以無定形狀態高度分散在聚合物中，目前已成功應用于多種上市藥物的制劑開發中。借助SDD技術，候選化合物藥片制劑的口服生物利用度提高了約30倍，為后續臨床應用奠定了堅實基礎。

合全藥業一體化CRDMO平臺的整合能力，使多個團隊能夠并行推進原料藥與制劑開發，高效協作，加速破解PROTAC?分子開發中的難題。最終，團隊僅用了12個月就完成了支持IND申請所需的候選藥物生產和制劑制備，順利供應首次人體臨床研究用藥，比合作伙伴原定時間提前了2個月。

超越蛋白降解：分子膠抑制劑獲突破性療法認定

TPD只是誘導接近機制在新藥開發中的一種應用。分子膠通過將靶點蛋白與呈遞蛋白（presenter proteins）結合，形成復合表面，從而突破傳統藥物對活性位點的依賴，讓小分子能夠靶向更多“不可成藥”的靶點，顯著拓展了治療可能性。

例如，Revolution Medicines公司研發的RAS抑制劑elironrasib成功招募了cyclophilin這一呈遞蛋白，實現了對激活狀態下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，用于治療攜帶

KRAS

G12C突變的非小細胞肺癌（NSCLC）患者。Elironrasib單藥治療在既往未接受KRAS抑制劑的經治NSCLC患者中達到56%的ORR和94%的疾病控制率（DCR）；與pembrolizumab聯用時，一線治療的ORR更是高達100%，顯示出可喜的初步療效。

Halda Therapeutics公司的調節誘導接近靶向嵌合體（RIPTAC）則代表另一種新策略。這類異雙功能分子的一端結合富集于癌細胞中的靶點蛋白，另一端結合細胞生存必需的關鍵蛋白。當細胞同時表達這兩種蛋白時，RIPTAC分子將兩者結合形成復合體，使關鍵蛋白失活，從而誘導癌細胞死亡。

今年8月，Halda Therapeutics宣布與VantAI達成研發合作，利用VantAI的人工智能和結構蛋白組學發現平臺，開發治療癌癥和免疫疾病的下一代RIPTAC藥物。

越來越多開發誘導接近藥物的公司開始利用人工智能技術加速新藥發現，除了Halda Therapeutics與VantAI的合作，Revolution Medicines在7月與Iambic Therapeutics也達成研發合作，利用Iambic公司基于AI的蛋白-配體結構預測模型和圖像神經網絡模型來發現創新候選藥物。今年8月，致力于分子膠藥物開發的Proxygen宣布與洛桑聯邦理工學院（EPFL）建立戰略研究合作關系。這一合作旨在將高通量體外篩選與先進計算設計相結合，以系統性地預測和驗證新底物-連接酶相互作用，并設計能夠誘導靶向蛋白降解的化學分子。

非降解性分子膠的開發也得到投資人的關注。今年9月，Rapafusyn Pharmaceuticals宣布完成4400萬美元A輪融資。該公司的RapaGlue平臺已展現出生成高協同非降解型分子膠的能力，這些分子膠具有較高的細胞膜通透性，可用于調控蛋白-蛋白相互作用、轉錄因子、轉運蛋白、離子通道、酶等多種難以成藥靶點。

一體化平臺助力分子膠早期發現

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

▲藥明康德分子膠發現平臺（圖片來源：參考資料[15]）

在分子膠藥物的早期發現過程中，藥明康德不僅依賴DNA編碼化合物庫進行篩選，還不斷引入并整合多種先進技術，以助力合作伙伴拓展分子膠藥物的發現能力。其中，親和篩選質譜（ASMS）提供無標記篩選手段。藥明康德構建了一個涵蓋超過37萬個小分子的廣譜化合物庫，通過比較這些分子在單蛋白與雙蛋白條件下的質譜信號差異，精準識別出能夠促進蛋白–蛋白相互作用的潛在分子膠候選物，從而識別出潛在促互作的小分子。

與此同時，公司還部署高通量篩選（HTS）技術。在“一孔一化合物”的自動化運行模式下，結合蛋白結合能力或降解能力等功能性實驗，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確性。通過將ASMS與HTS等多維篩選工具與DEL平臺深度融合，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進入分子膠研究視野，進一步拓寬了分子膠在多類靶點上的研發空間。

展望未來

Broad研究所聯合創始人Stuart Schreiber博士在2024年發表的一篇評論文章中指出，基于誘導接近作用的分子膠和雙功能化合物為藥物發現提供了創新模式。這一模式可以通過新穎的方式調控具有挑戰性的靶點，包括穩定、降解、易位、激活，以及重塑轉錄回路。對于精準醫療而言，這可能提供了一個獨特的機會，將“合適的藥物在合適的時間、用于合適的患者，在合適的組織中生效”這一理念變為現實。

藥明康德將繼續秉持“讓天下沒有難做的藥，難治的病”的愿景，依托全球研發基地與生產網絡，以獨特的一體化、端到端的CRDMO模式，助力包括靶向蛋白降解劑在內的誘導接近藥物的開發，幫助合作伙伴將科學創新轉化為惠及全球患者的變革性藥物。

CRDMO: Q3 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. To date, this platform has supported the development of more than 120 TPD molecules, with over 20 advancing to clinical stages. In recent years, induced proximity has extended beyond TPDs to include inhibitors for hard-to-drug targets and tissue-specific therapies. This article reviews the latest developments in Q3 2025 and highlights how WuXi AppTec’s integrated CRDMO platform helps overcome the unique challenges of developing induced-proximity medicines.

Targeted Protein Degradation: FDA Accepts NDA for a PROTAC? Therapy

In a major regulatory milestone, Arvinas and Pfizer announced that the U.S. FDA has accepted the New Drug Application (NDA) for the PROTAC? therapy vepdegestrant. The application covers patients with advanced or metastatic breast cancer who have received prior endocrine therapy and are ER+/HER2? with

ESR1

mutations. According to the companies, vepdegestrant is the first PROTAC? therapy to demonstrate clinical benefit in breast cancer. If approved, it will become the first FDA-approved PROTAC? estrogen receptor degrader.

Other companies are also making progress. C4 Therapeutics reported Phase 1 clinical results for its protein degrader cemsidomide in multiple myeloma. As of July 23, 2025, the objective response rate (ORR) was 40% in the 75 μg cohort and 50% in the 100 μg cohort. A registrational trial is planned for early 2026.

Meanwhile, Monte Rosa Therapeutics announced that the first subjects have been dosed in a Phase 1 study evaluating MRT-8102, a NEK7-directed molecular glue degrader being developed for the treatment of inflammatory conditions driven by the NLRP3 inflammasome, IL-1β, and IL-6. Adding to this progress, Monte Rosa published a paper in

Science

describing how its proprietary AI and ML engine identified human proteins potentially amenable to CRBN-mediated degradation. The findings, spanning diverse protein domains and classes, significantly broaden the actionable target space for molecular glue degrader discovery. On September 15, the company also announced an agreement to collaborate with Novartis to develop novel degraders for immune-mediated diseases.

While clinical advances are encouraging, TPDs still pose unique development hurdles. For example, due to their large molecular weight and structural complexity, PROTAC? compounds often suffer from poor solubility and suboptimal pharmacokinetics. The following case study illustrates how WuXi STA, an integral part of WuXi AppTec, collaborated with a partner to address these challenges effectively.

Addressing Key Bottlenecks in TPD Drug Development

Several years ago, a biotech company developing a PROTAC? candidate faced synthetic challenges and turned to WuXi STA for support. The goal was to complete the production of drug substance and clinical trial material within 14 months to support an IND filing and FIH trial. However, the original synthesis route involved 24 steps and yielded only 0.3%. Crystallization and purification proved difficult due to the compound’s unique structure.

Compounding the challenge, the candidate’s high molecular weight and poor solubility resulted in oral bioavailability of only 0.9%. Moreover, three steps in the synthesis relied on a palladium (Pd) catalyst, raising safety concerns and increasing production costs.

To resolve these issues, WuXi STA’s process chemistry, biocatalysis, and crystallization teams worked in concert to redesign the synthesis route, reducing the number of steps from 24 to 16 and replacing palladium with biocatalysts in two steps. To tackle crystallization bottlenecks, high-throughput crystallization screening identified suitable conditions that met both purity and yield requirements. These changes significantly improved the scalability and efficiency of the synthetic route while reducing costs.

Simultaneously, WuXi STA’s formulation team addressed the low oral bioavailability by exploring a range of enabling technologies and ultimately selected spray-dried dispersion (SDD) to prepare a solid dosage form. SDD disperses poorly soluble compounds in an amorphous state within a polymer matrix and has been successfully used in several approved drugs. With this approach, the candidate’s oral bioavailability improved by approximately 30-fold—supporting further clinical advancement.

Thanks to WuXi STA’s integrated CRDMO model, API process development and formulation were advanced in parallel by multiple teams working seamlessly together. Ultimately, they delivered IND-enabling materials and clinical trial materials within just 12 months—two months ahead of schedule.

Beyond Protein Degradation: Molecular Glue Inhibitor Receives Breakthrough Designation

Induced proximity is not limited to protein degradation. Molecular glues, which bind a target protein and a presenter protein to form composite binding surfaces, bypass the need to interact with active sites. This allows small molecules to reach a broader range of targets, including those once considered undruggable.

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.

In August, Halda announced a partnership with VantAI to apply AI and structural proteomics in the discovery of next-generation RIPTACs for cancer and immune diseases. Revolution Medicines also entered a collaboration with Iambic Therapeutics in July, leveraging AI-based protein-ligand prediction and neural network models to accelerate novel candidate discovery. In August, Proxygen announced a strategic research collaboration with EPFL (the Swiss Federal Institute of Technology in Lausanne). The collaboration aims to build a next-generation discovery paradigm that bridges high-throughput

in vitro

screening with state-of-the-art

in silico

design.

Non-degrading molecular glues also attracted investors’ attention. In September, Rapafusyn Pharmaceuticals announced the closing of its oversubscribed Series A financing round ($44 million). Its RapaGlue platform has demonstrated the ability to create highly cooperative non-degrading molecular glues with high cell membrane permeability to modulate protein–protein interactions, transcription factors, transporters, ion channels, enzymes, and others.

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

Outlook

Looking ahead, the potential of induced proximity continues to grow. In a 2024 commentary, Dr. Stuart Schreiber, co-founder of the Broad Institute, highlighted molecular glues and bifunctional compounds as an innovative paradigm in drug discovery—capable of stabilizing, degrading, translocating, activating targets, as well as rewiring transcriptional circuits. For precision medicine, this may enable the long-sought goal of delivering “the right drug to the right patient at the right time—and in the right tissue.”

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.

參考資料：

[1] Arvinas Announces FDA Acceptance of the New Drug Application for Vepdegestrant for the Treatment of ESR1m, ER+/HER2- Advanced Breast Cancer. Retrieved August 20, 2025, from https://www.globenewswire.com/news-release/2025/08/08/3130368/0/en/Arvinas-Announces-FDA-Acceptance-of-the-New-Drug-Application-for-Vepdegestrant-for-the-Treatment-of-ESR1m-ER-HER2-Advanced-Breast-Cancer.html

[2] C4 Therapeutics Reports Second Quarter 2025 Financial Results and Recent Business Highlights. Retrieved August 20, 2025, from https://ir.c4therapeutics.com/news-releases/news-release-details/c4-therapeutics-reports-second-quarter-2025-financial-results

[3] Monte Rosa Announces Publication in Science of Key Insights that Enable Next Generation Molecular Glue Degrader Medicines. Retrieved August 20, 2025, from https://ir.monterosatx.com/news-releases/news-release-details/monte-rosa-announces-publication-science-key-insights-enable

[4] Monte Rosa Therapeutics Announces First Subjects Dosed in Phase 1 Study of MRT-8102, a NEK7-Directed Molecular Glue Degrader for the Treatment of Multiple Inflammatory Diseases. Retrieved August 20, 2025, from https://ir.monterosatx.com/news-releases/news-release-details/monte-rosa-therapeutics-announces-first-subjects-dosed-phase-1

[5] SEED Therapeutics Named Finalist for 2025 Prix Galien USA “Best Start-Up” Award. Retrieved August 20, 2025, from https://seedtherapeutics.com/seed-therapeutics-named-finalist-for-2025-prix-galien-usa-best-start-up-award/

[6] Revolution Medicines Announces FDA Breakthrough Therapy Designation for Elironrasib. Retrieved August 20, 2025, from https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-fda-breakthrough-therapy-0

[7] Revolution Medicines Announces Publication of a Peer-Reviewed Research Paper in Science on the Discovery and Development of Zoldonrasib, a RAS(ON) G12D-Selective Inhibitor. Retrieved August 20, 2025, from https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-announces-publication-peer-reviewed

[8] VantAI and Halda Therapeutics Forge Alliance to Discover Next-Generation RIPTAC Medicines. Retrieved August 20, 2025, from https://haldatx.com/vantai-and-halda-therapeutics-forge-alliance-to-discover-next-generation-riptac-medicines/

[9] Arvinas Reports Second Quarter 2025 Financial Results and Provides Corporate Update. Retrieved August 20, 2025, from https://ir.arvinas.com/news-releases/news-release-details/arvinas-reports-second-quarter-2025-financial-results-and

[10] Targeted Protein Degrader. Retrieved August 20, 2025, from https://rcs.wuxiapptec.com/wp-content/uploads/RCS_Targeted-Protein-Degrader_20250818.pdf

[11] Revolution Medicines and Iambic Announce Technology and Research Collaboration Using Iambic’s AI Discovery Tools to Pursue New Drug Candidates. Retrieved August 27, 2025, from https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-and-iambic-announce-technology-and-research

[12] Schreiber (2024). Molecular glues and bifunctional compounds: Therapeutic modalities based on induced proximity. Cell Chemical Biology, DOI: 10.1016/j.chembiol.2024.05.004

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[14] Proxygen and EPFL Launch Strategic Collaboration to Advance AI-Driven Glue Discovery. Retrieved September 11, 2025, from https://www.globenewswire.com/news-release/2025/08/26/3139189/0/en/Proxygen-and-EPFL-Launch-Strategic-Collaboration-to-Advance-AI-Driven-Glue-Discovery.html

[15] Molecular Glues Discovery: Challenges and Opportunities. Retrieved July 4, 2025 from https://wuxibiology.com/resource/discovery-of-molecular-glues-challenges-and-opportunities/

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