编者按：过去几年，诱导接近（induced proximity）主要用于通过药物将靶蛋白与E3泛素连接酶拉近，让疾病相关蛋白被细胞自身的蛋白降解系统“销毁”。然而，诱导接近改变的不只是蛋白的稳定性，更是分子之间的相互作用关系。药物可以让一个蛋白被降解，也可以让两个蛋白形成新的复合体，从而抑制信号传导、稳定蛋白，甚至改变其位置或功能。
2026年第三季度，两款采用不同诱导接近机制的新药先后获得美国FDA批准，显示诱导接近正迈向多种作用机制的临床转化。以RAS三元复合体抑制剂和非降解型分子胶为代表的新策略，展现了诱导接近在非蛋白降解领域的发展潜力。
面对这些变化，药明康德依托一体化、端到端的CRDMO赋能平台，构建了覆盖蛋白降解靶向嵌合体、分子胶、调节诱导接近靶向嵌合体、抗体偶联降解剂等多种分子类型的能力体系，助力更多诱导接近药物加速走向临床、惠及患者。
RAS分子胶抑制剂与首款CELMoD疗法同月获批，多个诱导接近机制获得监管验证
今年5月，辉瑞（Pfizer）和Arvinas联合开发的Veppanu（vepdegestrant）获美国FDA批准，标志着双功能蛋白降解药物完成了从科学概念到上市药物的重要跨越。第三季度，诱导接近领域又连续迎来两个值得关注的监管里程碑。
8月13日，美国FDA加速批准百时美施贵宝（Bristol Myers Squibb）的Zenbexus（iberdomide），与daratumumab皮下注射制剂和dexamethasone联用，用于治疗既往接受过至少一线治疗、且治疗方案包含蛋白酶体抑制剂和免疫调节剂的多发性骨髓瘤成人患者。Iberdomide与E3泛素连接酶复合体的底物识别蛋白cereblon（CRBN）结合，促进转录因子Aiolos和Ikaros被募集、泛素化并由蛋白酶体降解。百时美施贵宝在新闻稿中指出，这是该公司的首款获批CRBN E3连接酶调节剂（CELMoD）疗法。
8月26日，Revolution Medicines开发的Rasonque（daraxonrasib）获FDA批准，用于治疗既往至少接受过一种全身性治疗，或不适合接受多药联合全身性治疗的转移性胰腺腺癌成人患者。与蛋白降解剂不同，daraxonrasib并不会把RAS送入蛋白酶体。它首先与伴侣蛋白cyclophilin A（CypA）结合形成二元复合物，随后结合处于活化、GTP结合状态的RAS形成三元复合体。这个复合体通过阻断RAS与下游效应蛋白的相互作用抑制RAS的信号传导。
Iberdomide通过调节E3连接酶的底物识别，促进靶蛋白降解； daraxonrasib则通过伴侣蛋白创造新的三元复合体，从功能上“封闭”活性RAS。它们使用不同效应系统、产生不同的生物学结果，却共享一个重要药物设计理念：药物除了直接结合靶蛋白上的特定口袋，还可以利用新的分子相互作用改变靶点的命运或功能。
从首款蛋白降解靶向嵌合体药物到CELMoD疗法和RAS靶向分子胶，基于诱导接近理念的不同药物设计策略接连获得监管验证，进一步验证了不同诱导接近策略的成药潜力。
不再只“销毁”蛋白，非降解型诱导接近加速进入产业验证
如果说蛋白降解是诱导接近领域最成熟的方向之一，那么2026年第三季度另一个明显变化，是非降解型诱导接近开始形成更加清晰的临床进展和产业化信号。
Daraxonrasib就是其中最直接的例子。它并不会导致RAS降解，而是借助CypA诱导形成RAS-药物-CypA三元复合体，用空间位阻效应阻止RAS与下游效应蛋白结合。
这种思路正在向更多RAS/MAPK通路药物延伸。
9月28日，默沙东（MSD）与思璞锐（SciBrunch Therapeutics）达成全球独家许可协议，获得口服KRAS G12D（ON）分子胶抑制剂SPR2015的全球开发、生产和商业化权益。根据协议，思璞锐将获得4亿美元首付款，交易潜在总额最高达21.3亿美元。
仅一天后，中外制药（Chugai）宣布与InxMed达成全球许可协议，将其发现的RAF-MEK分子胶SPYK04的全球独家开发、生产及商业化权利授予InxMed。与传统RAF或MEK抑制剂不同，SPYK04同时结合RAF和MEK，将两者“黏合”形成失活的RAF-MEK复合体，从而阻断肿瘤相关生长信号。
在肿瘤学之外，非降解型分子胶也开始进入其他疾病领域。Enveda开发的口服小分子ENV-294是一种非降解型分子胶，通过稳定一个此前未被药物靶向的免疫相关蛋白发挥作用。ENV-294在治疗中重度特应性皮炎的1b期临床试验中已经获得积极结果，在展现良好安全性的同时观察到改善皮损的临床活性。目前它正在特应性皮炎和哮喘患者中开展多项2期临床研究。
这些项目共同提示，诱导接近的应用正在逐渐从促进疾病相关蛋白降解，进一步拓展至通过调节蛋白相互作用改变蛋白功能。
从理性设计到系统化发现，诱导接近研发工具箱进一步扩展
分子胶的发现曾经在很大程度上依赖偶然性。随着CRBN等E3连接酶的作用机制、底物识别方式以及药物诱导蛋白相互作用的结构基础逐渐被解析，研究人员已经能够更有目的地优化分子胶的效力、选择性和底物募集能力。Iberdomide和mezigdomide等新一代CELMoD药物就是这种发展策略的重要代表。Iberdomide在今年第三季度获FDA批准，也进一步验证了这一发现策略的临床转化潜力。
在此基础上，本季度多项研究进一步拓展了这一探索方向：除了针对已知E3和底物进行结构优化，能否建立更加系统化的方法，主动寻找新的E3连接酶、新底物以及尚未被药物利用的蛋白相互作用？
8月发表于Nature的一项研究开发了一套基于多重质谱的分子胶筛选方法。研究人员将7种E3连接酶与5000个不同的小分子进行组合筛选，系统寻找药物诱导形成的新型E3连接酶与底物之间的相互作用，并从中发现了能够重新编程E3连接酶DCAF11的分子M12。M12可募集RNA解旋酶DDX18并促进其降解。与经典分子胶不同的是，M12本身需要经过谷胱甘肽S-转移酶介导的谷胱甘肽化，转化后的分子才能形成具有活性的分子胶。
这一研究的意义不只在于发现了一个新的分子胶。传统分子胶研究通常从一个已知化合物、E3连接酶或底物出发，而这套方法尝试同时扩大多个维度的搜索空间，在不同E3连接酶、大量化合物和潜在新底物之间寻找此前未知的诱导接近关系。M12的代谢激活机制还进一步提示，影响诱导接近的因素不仅包括化合物、靶点和E3连接酶，还可能涉及特定的细胞内代谢环境。
另一项8月发表于Nature Biotechnology的研究，则把搜索对象进一步从单个底物扩大到了蛋白组尺度的“潜在相互作用空间”。研究人员首先利用高通量蛋白互作检测方法GluePCA分析CRBN-泊马度胺复合体能够募集的蛋白，发现约210种锌指蛋白结构域或构建体能够与该复合体发生相互作用。随后，团队将基于人工智能的蛋白表面分析工具MaSIF-mimicry与GluePCA结合，在蛋白组尺度搜索潜在CRBN相互作用蛋白，最终识别出6种已知和43种此前未知的CRBN-泊马度胺结合蛋白。
值得注意的是，这些蛋白并不一定已经能够被有效降解。其中一些只是与CRBN-分子胶复合体发生较弱的“潜在相互作用”。研究人员提出，这些蛋白可以成为后续分子胶优化的起点。换句话说，发现思路正在发生变化：研究人员不一定要从一个已经能够实现蛋白降解的化合物开始，而可以先系统鉴定哪些蛋白具有被特定E3连接酶-分子胶复合体募集的潜力，再通过药物化学进一步增强这种相互作用，使其转化为具有药理意义的诱导接近事件。
筛选方法本身也在向更加贴近细胞功能的方向延伸。8月在线发表于ACS Chemical Biology的一项研究开发了PhenoDEL，将单珠单化合物DNA编码化合物库（OBOC-DEL）与单细胞光流控分析系统结合。与主要检测蛋白结合的传统DEL筛选不同，这一方法让携带单个DEL化合物的微珠与报告细胞在纳升级微腔中共同培养，并直接读取细胞内蛋白降解表型，再通过DNA条码追溯对应的化合物。作为概念验证，研究人员成功区分了能够和不能诱导报告蛋白降解的化合物。
这项方法目前仍属于早期概念验证，但它代表了另一个值得关注的方向：对于诱导接近药物而言，“是否结合”并不一定等于“能否产生所需功能”。如果能够把大规模化学空间筛选与细胞内功能表型更直接地连接起来，就有望帮助研究人员更早识别真正能够产生目标生物学效应的化合物。
从早期偶然发现的免疫调节剂，到基于CRBN机制开发的新一代CELMoD，分子胶药物发现已经经历了长期的机制解析和理性优化。第三季度更加值得关注的变化在于，研究人员正在这一基础上进一步拓展发现工具：从优化一个已知分子，走向系统搜索新的E3连接酶；从寻找一个已知底物，走向绘制更广泛的潜在相互作用网络；从检测分子与靶蛋白的结合，进一步拓展至直接筛选细胞功能表型。
一体化平台助力诱导接近药物开发
在靶向蛋白降解疗法十余年的产业转化历程中，药明康德几乎全程参与，为合作伙伴提供一体化赋能。在蛋白降解靶向嵌合体刚刚起步时，药明康德就前瞻性地布局相关能力和技术，搭建了集发现、合成、分析纯化和测试等能力于一体的赋能平台，助力全球合作伙伴高效推进药物从早期发现走向临床试验阶段。
药明康德一体化平台的能力不仅涵盖靶向蛋白降解分子，还包括分子胶以及多种新兴双功能分子。以分子胶药物发现为例，在早期研发阶段，无偏倚药物筛选的低命中率始终是一大挑战。为助力合作伙伴有效应对这一难题，药明康德采取了“双轨并进”的策略，构建起一套兼顾广度与深度的化合物库体系：一方面，通过多样化的DNA编码化合物库（DEL）大范围探索化学空间、寻找潜在苗头化合物；另一方面，借助聚焦化合物库精细化研究已知蛋白体系，提升发现效率。
在分子胶药物的早期发现过程中，药明康德不仅利用DNA编码化合物库进行筛选，还不断引入并整合多种先进技术，以助力合作伙伴拓展分子胶药物的发现能力。其中，亲和筛选质谱（ASMS）提供无标记筛选手段。药明康德构建了一个涵盖超过37万个小分子的广谱化合物库，通过比较这些分子在单蛋白与双蛋白条件下的质谱信号差异，筛选出能够促进蛋白相互作用的潜在分子胶候选物。
与此同时，公司还部署高通量筛选（HTS）技术。在“一孔一化合物”的自动化运行模式下，结合蛋白结合能力或降解能力等功能性实验，HTS能迅速锁定具备生物活性的候选分子，大幅提升筛选效率与准确性。通过将ASMS与HTS等多维筛选工具与DEL平台深度融合，药明康德打破了单一筛选方式的限制，让更多不同类型的靶点进入分子胶研究视野，进一步拓宽了分子胶在多类靶点上的研发空间。
伴随着新型靶向蛋白降解技术和诱导接近策略的持续涌现，药明康德紧跟科学前沿，迅速构建相关技术平台。如今，相关能力已涵盖蛋白降解靶向嵌合体、调节诱导接近靶向嵌合体、自噬靶向嵌合体、溶酶体靶向嵌合体、去泛素化酶靶向嵌合体、核糖核酸酶靶向嵌合体、磷酸化诱导嵌合小分子以及抗体偶联降解剂等主要分子类型。展望未来，药明康德将持续以一体化、端到端的CRDMO赋能平台，助力全球合作伙伴加速创新药物的研发生产进程，让科学突破更快为患者带来福祉。
Induced Proximity Drugs in Q3 2026: Industry Trends and How Integrated Platforms Support Development
Induced proximity drugs create or stabilize interactions between proteins to change their fate or function. The best-known application is targeted protein degradation, in which a molecule recruits a disease-associated protein to cellular degradation machinery. However, induced proximity can also inhibit signaling, stabilize proteins, or alter their localization or activity without removing them.
Q3 2026 highlighted three developments: regulatory validation of distinct proximity-based mechanisms, growing industry interest in non-degrading molecular glues, and more systematic methods for discovering productive protein interactions.Together, they suggest that induced proximity is becoming a broader drug design strategy rather than a field focused primarily on protein degradation.
Regulatory Milestones Validate Different Induced Proximity Mechanisms
Two FDA decisions in August illustrated how distinct cellular partners can drive different therapeutic outcomes.
On August 13, the FDA granted accelerated approval to a next-generation cereblon E3 ligase modulator for adults with multiple myeloma who had received at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.The approved regimen combines the modulator with an anti-CD38 antibody formulation and a corticosteroid.
This molecular glue binds cereblon, the substrate-recognition component of an E3 ubiquitin ligase complex, and promotes recruitment of the transcription factors Aiolos and Ikaros. Their subsequent ubiquitination and proteasomal degradation illustrate how a small molecule can redirect substrate recognition to produce a therapeutic effect.
On August 26, the FDA approved a RAS inhibitor for adults with metastatic pancreatic adenocarcinoma who had received at least one prior systemic therapy or were not candidates for multiagent systemic therapy.Its mechanism is different: the molecule binds the chaperone cyclophilin A, then engages active, GTP-bound RAS to form a ternary complex. This complex blocks interactions between RAS and downstream effectors rather than directing RAS to the proteasome.
These examples share a design principle, but not a biological outcome.One redirects an E3 ligase to remove selected proteins; the other uses a chaperone to inhibit signaling through a new molecular complex.Their approvalsdemonstrate that both strategies can be translated into approved therapies.
Non-Degrading Molecular Glues Attract Broader Industry Interest
Licensing activity during the quarter reinforced interest in proximity-based inhibition of the RAS/MAPK pathway.
A September 28 global license agreement for an investigational oral KRAS G12D (ON) inhibitor included a $400 million upfront payment and a total potential transaction value of $2.13 billion, including contingent milestones. The candidate was still in preclinical development, making the agreement a signal of investment in future development rather than evidence of clinical efficacy.
The following day, a separate worldwide licensing agreement focused on a RAF–MEK molecular glue. This compound binds RAF and MEK and promotes the formation of an inactive complex, suppressing proliferative signaling without relying on protein degradation. It illustrates another way to control the same signaling network by changing the relationship between pathway components.
Non-degrading molecular glues are also being explored outside oncology.An investigational oral compound for inflammatory diseases has shown encouraging activity and tolerability in a small, open-label Phase 1b study in patients with moderate-to-severe atopic dermatitis and has advanced into Phase 2 development for atopic dermatitis and asthma. These early findings support further study; they do not yet establish efficacy in larger controlled populations.
The broader implication is thatinduced proximity can be used not only to trigger protein degradation but also to create or stabilize interactions that alter protein function.The selection of protein partners and the design of the resulting complex should be guided by the intended biological outcome.
Molecular Glue Discovery Becomes More Systematic
Molecular glue discovery has historically depended heavily on unexpected biological observations. Mechanistic and structural insights have since enabled more deliberate optimization of known systems. Research published during Q3 advanced more systematic approaches to identifying new ligase–substrate interactions and their cellular effects.
An August study published in Nature used multiplexed mass spectrometry to screen seven E3 ligases against approximately 5,000 small molecules. The approach identified a compound that recruits the RNA helicase DDX18 to the DCAF11-associated E3 ligase machinery and promotes its degradation.
The compound requires glutathione S-transferase-mediated glutathionylation to become an active molecular glue. This finding adds an important dimension to discovery: cellular metabolism can help determine whether an otherwise unproductive molecule can promotes a productive protein–protein interaction.
The study therefore provides both a screening strategy and a mechanistic lesson.Searching across multiple ligases and compounds can uncover previously unknown recruitment relationships, while biochemical assays may need to account for cellular activation processes.
A study in Nature Biotechnology combined a high-throughput protein interaction assay, GluePCA, with an artificial intelligence-based protein surface analysis tool, MaSIF-mimicry. Initial screening identified approximately 210 zinc-finger constructs capable of interacting with a cereblon–molecular glue complex. Broader computational screening and experimental testing identified six known and 43 previously unrecognized binding constructs.
These interactions should not be equated with efficient degradation of the corresponding intact proteins. Some represent weak or latent recruitment potential, and assays using protein fragments do not establish that full-length targets will behave identically.
Nevertheless,such maps can provide starting points for medicinal chemistry. Instead of beginning only with a compound that already degrades a target, researchers canfirst identifya potentially productive protein recruitment and then test whether optimization can optimize it to achieve selective target degradation.
An August publication in ACS Chemical Biology described PhenoDEL, an early screening approach that combines a one-bead–one-compound DNA-encoded library with single-cell optofluidic analysis. Individual compound-bearing beads are cocultured with reporter cells in nanoliter-scale chambers, allowing intracellular degradation responses to be linked to compound identity through DNA barcodes.
The proof-of-concept experiments distinguished compounds that induced reporter degradation from those that did not.The method remains at an early stage, but it addresses a central discovery problem: protein binding does not necessarily produce the desired cellular function.
Together, these studies point toward complementary discovery strategies—expanding the range of E3 ligases available for molecular glue discovery, mapping potential recruitment partners, and screening functional responses directly. Their value will depend on how effectively these interactions translate into selective pharmacological activity.
Integrated Platforms Help Advance the Development of Induced Proximity Drugs
Throughout more than a decade of progress in targeted protein degradation, WuXi AppTec has been deeply involved at every step, providing partners with fully integrated, end-to-end support. Even in the early days of proteolysis targeting chimera research, WuXi AppTec proactively invested in relevant capabilities, establishing a comprehensive platform that spans discovery, synthesis, purification, and testing.
WuXi AppTec’s integrated platform supports not only proteolysis targeting chimera 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
With the continued emergence of innovative induced proximity technologies, WuXi AppTec remains closely aligned with the scientific frontier and has rapidly built related technology platforms. Today, its capabilities cover major molecular modalities including proteolysis targeting chimeras, regulated induced proximity targeting chimeras, autophagy-targeting chimeras, lysosome-targeting chimeras, deubiquitinase-targeting chimeras, ribonuclease-targeting chimeras, phosphorylation-inducing chimeric small molecules, and degrader-antibody conjugates. Looking ahead, WuXi AppTec will continue leveraging its integrated, end-to-end CRDMO enabling platform to help global partners accelerate the research, development, and manufacturing of innovative medicines—bringing scientific breakthroughs to patients more quickly.
Key Takeaways:
Q3 2026 brought regulatory milestones for two distinct induced proximity mechanisms: cereblon-mediated protein degradation and non-degrading RAS inhibition. These approvals strengthen the clinical foundation for medicines that change protein function by creating new molecular interactions.
The field is expanding beyond protein degradation, and discovery approaches are becomes increasingly systematic. Non-degrading molecular glues are attracting licensing activity, and new screening approaches are exploring alternative E3 ligases, potential protein partners, and cellular functional responses.
Translating these advances into medicines requires more than productive complex formation. Integrated discovery, biology, drug metabolism and pharmacokinetics (DMPK), bioanalysis, and chemistry, manufacturing, and controls (CMC) capabilities can help connect mechanism, exposure, selectivity, and manufacturability.
参考资料：
[1] Hojong Yoon et al, DCAF11-dependent molecular glue degrader activated by glutathionylation, Nature (2026). DOI: 10.1038/s41586-026-10873-1
[2] Pius Galli et al, Proteome-wide identification of the druggable CRBN interactome, Nature Biotechnology (2026). DOI: 10.1038/s41587-026-03237-7
[3] Yuichi Onda et al, PhenoDEL: A Novel Screening Strategy Based on Intracellular Protein Degradation Activity, ACS Chemical Biology (2026). DOI: 10.1021/acschembio.6c00234
[4] Edmond R. Watson et al, Molecular glue CELMoD compounds are regulators of cereblon conformation, Science (2022). DOI: 10.1126/science.add7574
[5] FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. Retrieved October 1, 2026, from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vepdegestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast
[6] FDA grants accelerated approval to iberdomide with daratumumab and hyaluronidase-fihj and dexamethasone for multiple myeloma. Retrieved October 1, 2026, from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-iberdomide-daratumumab-and-hyaluronidase-fihj-and-dexamethasone
[7] U.S. FDA Grants Accelerated Approval to Bristol Myers Squibb's First CELMoD Therapy ZENBEXUS™, in Combination with Daratumumab and Hyaluronidase-fihj and Dexamethasone (ZDd) for Patients with Multiple Myeloma, as Early as First Relapse. Retrieved October 1, 2026, from https://news.bms.com/news/corporate-financial/2026/U-S--FDA-Grants-Accelerated-Approval-to-Bristol-Myers-Squibbs-First-CELMoD-Therapy-ZENBEXUS-in-Combination-with-Daratumumab-and-Hyaluronidase-fihj-and-Dexamethasone-ZDd-for-Patients-with-Multiple-Myeloma-as-Early-as-First-Relapse/default.aspx
[8] FDA approves daraxonrasib for metastatic pancreatic adenocarcinoma. Retrieved October 1, 2026, from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daraxonrasib-metastatic-pancreatic-adenocarcinoma
[9] MSD Enters into Exclusive Global License Agreement with SciBrunch Therapeutics for SPR2015, an Investigational Oral KRAS G12D (ON) Inhibitor. Retrieved October 1, 2026, from https://www.msd.com/news/msd-enters-into-exclusive-global-license-agreement-with-scibrunch-therapeutics-for-spr2015-an-investigational-oral-kras-g12d-on-inhibitor/
[10] Chugai and InxMed Enter into Global License Agreement for RAF-MEK Molecular Glue SPYK04. Retrieved October 1, 2026, from https://www.chugai-pharm.co.jp/english/news/detail/20260929170000_1254.html
[11] Enveda’s Positive Phase 1B Results for ENV-294, a Potential First-in-Class Oral Therapy for Moderate-to-Severe Atopic Dermatitis, Were Presented at AAD Innovation Academy; Additional Details to Be Shared at EADV. Retrieved October 1, 2026, from https://enveda.com/news/envedas-positive-phase-1b-results-for-env-294-a-potential-first-in-class-oral-therapy-for-moderate-to-severe-atopic-dermatitis-were-presented-at-aad-innovation-academy-additional-details-t/
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