编者按：诱导接近（induced proximity）机制通过将蛋白或核酸拉近形成复合体，从而调控靶点功能。基于这一机制开发的靶向蛋白降解剂（TPD）已成为新药研发的热点之一。与传统抑制剂不同，它们无需直接抑制靶蛋白活性，而是通过降解疾病相关蛋白，有望靶向许多长期被认为“不可成药”的靶点。药明康德在TPD技术刚刚起步时，就开始布局相关能力和技术，积累了丰富的成功经验，搭建起集发现、合成、分析纯化和测试等能力于一体的一站式赋能平台。本文将回顾2026年第一季度诱导接近领域的最新进展，并介绍药明康德的一体化CRDMO平台如何高效解决诱导接近药物开发过程中的诸多挑战。
新一代分子胶有望今年获批，靶向蛋白降解在神经退行性疾病领域获得概念验证
今年2月，百时美施贵宝（Bristol Myers Squibb）宣布，美国FDA已受理其在研E3泛素连接酶cereblon（CRBN）调节剂（CELMoD）iberdomide联合标准治疗（daratumumab+地塞米松）用于复发或难治性多发性骨髓瘤（RRMM）的（NDA）。FDA有望在今年8月17日前完成审评。新闻稿指出，iberdomide有望成为首个获批的CELMoD类药物。Iberdomide是一种高效的CELMoD类药物，在结构上与来那度胺（lenalidomide）和泊马度胺（pomalidomide）相似。与来那度胺或泊马度胺相比，iberdomide与CRBN的结合亲和力提高约20倍，并可诱导CRBN发生构象改变，从而更高效地募集底物并促进Ikaros和Aiolos蛋白的降解。
百时美施贵宝的另一款CELMoD药物mezigdomide在3期临床试验SUCCESSOR-2中也获得积极结果。Mezigdomide联合carfilzomib和dexamethasone（MeziKd），在RRMM患者中，与单用carfilzomib和dexamethasone（Kd）相比，在无进展生存期（PFS）方面显示出统计学显著且具有临床意义的改善。
百时美施贵宝之外，Monte Rosa Therapeutics公司的分子胶降解剂MRT-2359在1/2期临床试验中也获得。MRT-2359与恩扎卢胺（enzalutamide）联用，在既往接受多线治疗、携带雄激素受体（AR）突变的转移性去势抵抗性前列腺癌（mCRPC）患者中，达到100%的疾病控制率（DCR）。
在癌症领域之外，靶向蛋白降解药物在神经退行性疾病领域也获得概念验证。Arvinas在今年3月公布了在研蛋白降解剂ARV-102的。该候选药物旨在特异性靶向并降解富含亮氨酸重复序列激酶2（LRRK2），用于治疗帕金森病（PD）。研究结果显示，在接受治疗的PD患者中，ARV-102在所有给药剂量下均可在第14天实现脑脊液（CSF）中LRRK2水平约50%或以上的降低，并在第28天持续维持这一降幅。
开发创新靶向蛋白降解策略，多家新锐完成融资或达成研发合作
在2026年第一季度，多家专注于开发创新蛋白降解策略和诱导接近药物的新锐完成融资。这些公司力图开拓具有差异化的靶向蛋白降解方式，并进一步扩展靶向蛋白降解的靶点范围。其中，EpiBiologics公司宣布完成1.07亿美元的B轮融资。该公司专有的EpiTAC平台是一种模块化双特异性抗体系统，生成的双特异性抗体的一端与靶点蛋白结合，另一端与在特定组织中富集的降解受体结合，从而以组织特异性的方式实现致病性细胞外蛋白的靶向降解。其在研疗法EPI-326是一款能够在肿瘤组织中降解EGFR的双特异性抗体，在临床前研究中已经表现出强劲且持久的疗效，并具有良好的安全性和药代动力学特征，预计在今年开展首个人体临床试验。
Enodia Therapeutics公司在今年年初完成2070万欧元的种子轮融资。该公司专注于开发选择性调控Sec61转位通道（Sec61 translocon）的药物。在蛋白质合成过程中，分泌蛋白和跨膜蛋白会通过该通道进入分泌通路。通过靶向这一机制，Enodia能够在疾病发生的上游阶段进行干预，特异性降解潜在致病蛋白，同时不影响关键的生理功能。Enodia公司在今年3月从Kezar Life Sciences收购了其基于Sec61通路的发现和开发项目。此次收购将使Enodia能够进一步深入理解Sec61选择性作用机制，从而拓展生物学与转化研究方面的认知，并加速推进关键临床里程碑的实现。
Laigo Bio在今年年初完成了1700万欧元超额认购种子轮融资。该公司的SureTACs平台生成的双特异性抗体能够同时与靶点膜蛋白和在细胞膜上表达的E3连接酶结合，从而给细胞膜蛋白打上泛素“标签”，诱导其被溶酶体降解。
Proxima（原VantAI）公司在1月完成8000万美元的种子轮融资，基于其人工智能（AI）驱动的药物发现平台开展新一代诱导接近药物的发现与开发。该公司明确表示将不局限于靶向蛋白降解剂的开发，而将探索诱导接近机制更为广泛的应用。
图片来源：123RF
大型药企仍然在蛋白降解领域持续布局。今年年初，强生（Johnson & Johnson）公司与TRIANA Biomedicines达成研发合作，共同发现和开发针对难以成药的肿瘤学靶点的新一代分子胶降解剂。益普生（Ipsen）在1月也与Origami Therapeutics公司达成研发协议，共同开发治疗一种罕见遗传性神经退行性疾病的小分子靶向蛋白降解疗法。赛诺菲（Sanofi）在今年2月对格博生物（GluBio Therapeutics）进行了3000万美元，支持其治疗镰状细胞病的分子胶降解剂GLB-005和GLB-007的开发。格博生物授予赛诺菲优先谈判权（ROFN），以就潜在的GLB-005和GLB-007开展相关研究、开发、生产及商业化的独家许可进行谈判。
随着诱导接近机制不断拓展至更广泛的靶点类型和疾病领域，其分子设计复杂性与体内行为不确定性也显著提升。从分子胶和双功能降解剂，到细胞外或组织特异性降解策略，这类创新分子在跨膜渗透、分布、代谢及暴露-药效关系等方面均对研发体系提出了更高要求。如何在早期阶段准确理解其ADME特征，并在复杂机制与临床转化之间建立清晰关联，正成为推动诱导接近药物成功开发的关键。
一体化平台助力靶向蛋白降解药物开发
药明康德药物代谢与动力学部（DMPK）在靶向蛋白降解药物分析与体内行为表征方面具备系统化、前瞻性的研究能力，能够全面应对这类大分子化合物的复杂ADME/药代特性挑战。双功能性靶向蛋白降解大分子常因分子量高、溶解度低、极性与疏水性区域共存以及体内易发生多种代谢途径而给传统DMPK分析带来难度。药明康德DMPK团队基于对靶向蛋白降解技术本质及药代影响因素的深入理解，构建了包括体内暴露、稳态分布、清除机制、代谢途径与药效相关暴露分析的整套策略框架，并通过高灵敏质谱分析、同位素标记追踪与体内外结合模型等技术路线揭示靶向蛋白降解分子体内行为规律。
在具体实施方面，团队针对靶向蛋白降解分子体内复杂代谢路径开展特定的质谱定性/定量方法开发，结合体内酶动力学与转运机制研究，准确识别主要代谢物及消除通路，形成从早期候选筛选到临床前全面DMPK评估的闭环服务。此外，药明康德DMPK通过整合药效暴露关系（PK/PD）与靶点占有率分析，为优化剂量策略与降低临床风险提供强有力的数据支持。这种从机制洞察到实验方法与数据解读的一体化能力，使得药明康德 DMPK平台能够为合作伙伴在复杂靶向蛋白降解药物开发过程中提供高质量、高确定性的药代研究支持，有效提升项目决策效率与研发成功率。
伴随着创新靶向蛋白降解技术的持续涌现，药明康德紧跟科学前沿，迅速构建相关技术平台，如今能力已涵盖PROTAC®、分子胶、AUTAC、LYTAC、DUBTAC、RIBOTAC、PHICS以及DAC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。
Q1 2026 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. This article reviews progress in the induced proximity field in Q1 2026 and highlights how WuXi AppTec’s integrated CRDMO platform helps overcome the unique challenges of developing induced proximity medicines.
Next-Generation Molecular Glues May Gain Approval This Year; Targeted Protein Degradation Achieves Proof-of-Concept in Neurodegenerative Diseases
In February this year, Bristol Myers Squibb announced that theU.S. FDA had accepted the New Drug Application (NDA) for its investigational E3 ubiquitin ligase cereblon (CRBN) modulator (CELMoD) iberdomide in combination with standard therapy (daratumumab + dexamethasone) for the treatment of relapsed or refractory multiple myeloma (RRMM).The FDA is expected to complete its review by August 17 this year. According to the press release, iberdomide may become the first approved CELMoD drug. Iberdomide is a potent CELMoD agent structurally related to lenalidomide and pomalidomide. Compared with these earlier agents, iberdomide exhibits approximately 20-fold higher binding affinity to CRBN and can induce conformational changes in the protein, enabling more efficient substrate recruitment and promoting the degradation of the transcription factors Ikaros and Aiolos.
Another CELMoD drug from Bristol Myers Squibb, mezigdomide, has also delivered positive results in the Phase 3 SUCCESSOR-2 clinical trial. When combined with carfilzomib and dexamethasone (MeziKd), the regimen demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in RRMM patients compared with carfilzomib and dexamethasone alone (Kd).
Beyond Bristol Myers Squibb, molecular glue degraders are also progressing across the industry. Monte Rosa Therapeutics reported encouraging results from a Phase 1/2 clinical trial of its molecular glue degrader MRT-2359. In combination with enzalutamide,MRT-2359 achieved a 100% disease control rate (DCR) in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) harboring androgen receptor (AR) mutations.
Outside oncology, targeted protein degradation has also demonstrated proof-of-concept in neurodegenerative diseases. Arvinas released Phase 1 clinical trial data in March for its investigational protein degrader ARV-102, designed to selectively target and degrade leucine-rich repeat kinase 2 (LRRK2) for the treatment of Parkinson’s disease (PD).The results showed that in treated PD patients, ARV-102 reduced LRRK2 levels in cerebrospinal fluid (CSF) by approximately 50% or more across all dose levels by Day 14, with the reduction maintained through Day 28.
Innovative Targeted Protein Degradation Strategies Drive Financing and R&D Collaborations
In the first quarter of 2026, several emerging companies focused on novel protein degradation strategies and induced proximity therapeutics completed financing rounds.These companies aim to develop differentiated approaches to targeted protein degradation and further expand the range of degradable targets.
Among them, EpiBiologics announced the completion of a $107 million Series B financing. Its proprietaryEpiTAC platform is a modular bispecific antibody system in which one arm binds a target protein while the other engages a degradation receptor enriched in specific tissues, enabling tissue-specific degradation of pathogenic extracellular proteins.Its investigational therapy EPI-326, a bispecific antibody designed to degrade EGFR in tumor tissues, has demonstrated strong and durable efficacy in preclinical studies, along with favorable safety and pharmacokinetic profiles. The company expects to initiate its first human clinical trial later this year.
Enodia Therapeutics completed a €20.7 million seed financing round earlier this year.The company focuses on developing drugs that selectively regulate the Sec61 translocon, a channel through which secreted and transmembrane proteins enter the secretory pathway during protein synthesis.By targeting this mechanism, Enodia aims to intervene at an upstream stage of disease biology, enabling the selective degradation of pathogenic proteins while preserving essential physiological functions. In March, Enodia acquired discovery and development programs based on the Sec61 pathway from Kezar Life Sciences. The acquisition is expected to deepen understanding of the selective mechanisms of Sec61 modulation and accelerate key clinical milestones.
Laigo Bio also completed an oversubscribed €17 million seed financing round earlier this year. ItsSureTACs platform generates bispecific antibodies capable of simultaneously binding target membrane proteins and E3 ligases expressed on the cell membrane, thereby tagging membrane proteins with ubiquitin and inducing lysosomal degradation.
Meanwhile, Proxima completed an $80 million seed financing round in January to advance the discovery and development of next-generation induced proximity therapeutics using its artificial intelligence-driven drug discovery platform.The company has stated that it will not limit its efforts to targeted protein degraders but will explore broader applications of induced proximity mechanisms.
Large pharmaceutical companies continue to expand their presence in the protein degradation field. Earlier this year, Johnson & Johnson entered a research collaboration with TRIANA Biomedicines to discover and develop next-generation molecular glue degraders targeting difficult-to-drug oncology targets. Ipsen also signed a research agreement in January with Origami Therapeutics to develop small-molecule targeted protein degraders for a rare hereditary neurodegenerative disease. In February, Sanofi made a $30 million strategic equity investment in GluBio Therapeutics to support the development of molecular glue degraders GLB-005 and GLB-007 for the treatment of sickle cell disease. GluBio granted Sanofi a right of first negotiation (ROFN) for an exclusive license covering research, development, manufacturing, and commercialization of GLB-005 and GLB-007.
As induced proximity mechanisms expand to broader target classes and disease areas, the complexity of molecular design and the uncertainty of in vivo behavior are increasing. From molecular glues and bifunctional degraders to extracellular or tissue-specific degradation strategies, these innovative molecules present higher demands on drug development systems in areas such as membrane permeability, distribution, metabolism, and exposure–response relationships. Accurately understanding ADME characteristics at an early stage and establishing clear links between complex mechanisms and clinical translation are becoming key to the successful development of induced proximity therapeutics.
Integrated Platform Accelerates the Development of Targeted Protein Degraders
WuXi AppTec DMPK has established a comprehensive evaluation framework specifically designed to address the unique analytical and pharmacokinetic challenges of targeted protein degraders such as bifunctional targeted protein degraders. Owing to their bifunctional structure, high molecular weight, poor solubility, and complex absorption and metabolism behaviors, these molecules often fall outside traditional small-molecule DMPK paradigms. Leveraging a deep mechanistic understanding of event-driven pharmacology and extensive experience with novel modalities, WuXi AppTec DMPK has developed a systematic research strategy integrating physicochemical characterization, in vitro ADME profiling, in vivo pharmacokinetic studies, metabolite identification, and exposure–response analysis to support rational optimization throughout preclinical development.
The platform combines tailored experimental design, advanced bioanalytical workflows, and cross-disciplinary collaboration to accurately characterize key properties such as permeability limitations, high plasma protein binding, metabolic pathways, and linker-related metabolite risks that are critical to the success of bifunctional targeted protein degraders. By integrating in vitro and in vivo data with robust PK/PD interpretation and strategic decision support, WuXi AppTec DMPK helps partners shorten development timelines while improving translational confidence. This end-to-end capability positions WuXi AppTec as a strategic partner for advancing next-generation targeted protein degradation therapies from discovery optimization to clinical development with greater efficiency and predictability.
With the continued emergence of innovative targeted protein degradation 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 PROTAC®, molecular glues, AUTAC, LYTAC, DUBTAC, RIBOTAC, PHICS, and DAC. 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.
参考资料：
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[5] Monte Rosa Therapeutics Presents Updated Clinical Data from Phase 1/2 Study of MRT-2359 in Combination with Enzalutamide in Heavily Pretreated Metastatic Castration-Resistant Prostate Cancer Patients at ASCO Genitourinary Cancers Symposium (ASCO GU). Retrieved February 24, 2026 from https://www.globenewswire.com/news-release/2026/02/24/3243353/0/en/Monte-Rosa-Therapeutics-Presents-Updated-Clinical-Data-from-Phase-1-2-Study-of-MRT-2359-in-Combination-with-Enzalutamide-in-Heavily-Pretreated-Metastatic-Castration-Resistant-Prost.html
[6] Bristol Myers Squibb Announces Positive Phase 3 Results from the SUCCESSOR-2 Study of Oral Mezigdomide in Relapsed or Refractory Multiple Myeloma. Retrieved March 9, 2026, from https://www.businesswire.com/news/home/20260308945507/en/Bristol-Myers-Squibb-Announces-Positive-Phase-3-Results-from-the-SUCCESSOR-2-Study-of-Oral-Mezigdomide-in-Relapsed-or-Refractory-Multiple-Myeloma
[7] Arvinas Announces Positive Phase 1 Data for ARV-102 Showing Greater Than 50% LRRK2 Degradation in the CSF of Patients with Parkinson’s Disease Treated for 28 Days. Retrieved March 18, 2026 from https://www.globenewswire.com/news-release/2026/03/18/3258013/0/en/Arvinas-Announces-Positive-Phase-1-Data-for-ARV-102-Showing-Greater-Than-50-LRRK2-Degradation-in-the-CSF-of-Patients-with-Parkinson-s-Disease-Treated-for-28-Days.html
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