Anagrelide Hydrochloride

在生物系统中，“距离”决定功能。分子彼此靠近并形成组合，是几乎所有生命调控过程的核心。诱导邻近（induced proximity）治疗模式，正是利用多特异性小分子或生物制品，通过促成生物大分子间的相互作用，借助机体原有通路来调控靶标功能。过去几十年，这一模式快速发展，突破了传统依赖“占位结合”（occupancy-driven）的药理学框架，为药物研发打开了全新的可能性。本文将基于《自然》子刊Nature Reviews Drug Discovery近期发布的综述，带您了解这一前沿领域的最新进展。 药物发现的新逻辑 传统小分子药物通常依赖直接占据靶点的活性口袋，以激动或抑制其功能。然而，据估计，约80%的蛋白质缺乏可成药的结合位点，因此长期被视为“难以成药”。而诱导邻近机制的提出，则显著改变这一药理学逻辑：药物不再只是抑制或激活，而是通过“撮合”两类生物大分子在细胞内相遇，激活天然信号通路，改变蛋白功能或水平。由此，研究者能够通过重塑细胞内蛋白网络，影响过去无法触及的靶点，实现更广泛的治疗可能。 从机制上看，这类药物主要分为两大类：单价分子胶（molecular glues）与双功能分子（bifunctional molecules）。后者既包括化学小分子，也涵盖生物大分子（如双特异性抗体），共同构成了诱导邻近策略的核心。 分子胶：从天然启示到理性设计 天然产物型分子胶 早在20世纪80年代，免疫抑制剂环孢素A（cyclosporin A）和他克莫司（tacrolimus）就被发现可通过与免疫亲和蛋白结合，抑制磷酸酶calcineurin的活性，从而实现免疫调控。随后，科学家发现雷帕霉素（rapamycin）能将FKBP12与mTOR连接，抑制其功能，从而调节免疫反应与细胞衰老相关通路。此类药物衍生出一系列如依维莫司（everolimus）的雷帕霉素类似物（rapalogs），这些药物至今仍在临床广泛应用。 除了抑制功能，分子胶还可稳定关键蛋白结构。例如，紫杉醇（paclitaxel）即通过稳定α/β微管蛋白的结合从而抑制细胞分裂。而fusicoccin A等则通过增强14-3-3蛋白与其配对蛋白的相互作用，实现特定通路激活或抑制。 图片来源：123RF 合成降解型分子胶 推动分子胶重新走向舞台中心的，是沙利度胺（thalidomide）及其衍生物来那度胺（lenalidomide）和泊马度胺（pomalidomide）的再发现。研究显示，它们通过与E3泛素连接酶受体cereblon（CRBN）结合，诱导其降解Ikaros家族转录因子，从而发挥抗肿瘤作用。这一机制的揭示不仅阐明了沙利度胺导致胎儿畸形的分子原因（即SALL4被异常降解），也奠定了后续免疫调节药物（IMiDs）开发的基础。 随着结构生物学的进步，IMiDs与CRBN结合的关键残基与构象变化被进一步解析，为新一代分子胶的理性设计提供了蓝图。例如，伊贝度胺（iberdomide）、mezigdomide与avadomide等分子在此基础上进行结构优化，显著提升了靶标降解的选择性与抗肿瘤活性，也展示出更优的药代动力学与临床潜力。 除IMiDs外，芳基磺酰胺类分子如E7820也展现出类似机制——通过诱导E3底物受体DCAF15与RNA结合蛋白RBM39形成复合体，从而促进后者降解，展现出显著的抗癌潜力。目前，E7820正在急性髓系白血病（AML）及骨髓增生异常综合征的2期临床中评估。 与此同时，新一代分子胶降解剂正不断拓展靶点空间。拜耳（Bayer）旗下的BAY 3605349（曾用名VVD-130037）即是一款作用于NRF2通路的创新分子胶。NRF2是一种调控细胞应激防御的转录因子，但其持续激活常见于肺癌及上呼吸道肿瘤中。该分子可与底物适配蛋白KEAP1共价结合，稳定KEAP1与E3连接酶CUL3的相互作用，从而增强NRF2降解。目前，BAY 3605349处于针对NRF2依赖性实体瘤的1期临床试验阶段。 合成非降解型分子胶 合成分子胶也可通过稳定或抑制机制发挥作用。例如，阿那格雷（anagrelide）是一种小分子磷酸二酯酶3A（PDE3A）抑制剂，于1997年获批用于治疗血小板增多症等血小板相关疾病。另一代表性分子trametinib（GSK112012）是一种获批用于癌症治疗的MEK抑制剂，其通过稳定MEK1/2激酶与RAS抑制因子KSR之间的相互作用来阻断RAS通路。 此外，RAS（ON）多重选择性抑制剂daraxonrasib（RMC-6236）可将RAS蛋白招募至环孢菌素A（cyclophilin A）上以实现间接抑制。今年9月所公布的临床试验数据显示，在二线及以上（2L+）转移性胰腺导管腺癌（PDAC）中，携带RAS G12X突变或携带任何RAS突变并接受daraxonrasib治疗的患者，其疾病控制率（DCR）分别可达92%与95%。目前，daraxonrasib单药在二线转移性PDAC中的注册性3期临床试验RASolute 302正在进行中，预计今年完成全球患者入组，并于2026年公布数据。 双功能诱导邻近药物：从PROTAC到RNA靶向 双功能化合物由两个独立的靶向配体组成，可诱导特定分子间空间邻近。小分子策略包括化学诱导二聚体（CIDs）、蛋白降解靶向嵌合体（PROTACs）及RNA靶向降解分子等模式；生物大分子策略则包括纳米抗体偶联物与双特异性抗体。限于篇幅，本文仅专注于小分子模式的介绍： 化学诱导二聚体（CIDs） 最早的“双头分子”探索可追溯至20世纪90年代，研究者通过合成同源与异源两类化学诱导二聚体开启了这类分子的初步实践。1993年，化合物FK506的同源二聚体FK1012被证实可诱导FKBP12二聚并实现功能性抑制。二十多年后，机理相近的化合物rimiducid获得孤儿药资格，被用于CAR-T疗法的药理学“开/关”开关：通过在CAR-T细胞内化学诱导FKBP–caspase 9融合蛋白二聚化，快速触发细胞凋亡，从而实现可控的安全管理。这些早期双功能化合物为后续多样化的双功能策略铺平了道路，推动诱导近邻技术从概念走向应用。 蛋白质降解靶向嵌合体（PROTAC） 自2001年问世以来，PROTAC技术已成为靶向蛋白降解的主流模式。现代PROTAC通过连接靶蛋白配体与E3连接酶配体（如CRBN或VHL）形成三元复合体，触发泛素化降解。代表性药物包括雌激素受体降解剂vepdegestrant（ARV-471）和雄激素受体降解剂luxdegalutamide（ARV-766）。其中前者用于治疗雌激素受体阳性（ER+）/人表皮生长因子受体2阴性（HER2-）、ESR1突变的晚期或转移性乳腺癌的新药申请（NDA）已在今年8月获美国FDA受理；而后者目前则处于前列腺癌的2期临床阶段。 目前有超过30款PROTAC分子已进入临床试验阶段，适应症涵盖肿瘤、自身免疫及神经退行性疾病等。PROTAC分子的优势在于其具催化性、并可在低剂量下持续作用，并具克服耐药突变的能力。但这类分子同时也存在分子量过大、细胞通透性差等成药性挑战。研究者正通过分子内氢键设计等方法改善这类分子的药代动力学性质。 靶向RNA的双功能分子 在RNA层面，研究者提出可靶向降解特定RNA的核糖核酸酶靶向嵌合体（RIBOTAC）平台。即通过小分子同时结合RNA与RNase L，实现RNA选择性降解。虽然这类治疗模式目前仍处于概念验证阶段，但已在miRNA-21等肿瘤相关靶点上展现初步的治疗前景。 应用拓展与未来展望 目前已知的E3连接酶超过600种，然而真正用于PROTAC设计的仍是少数。为扩大可降解靶点范围并缓解耐药问题，研究人员正积极探索HSP90、IAPs、芳烃受体等非典型E3连接酶系统。与此同时，诱导邻近策略也正在从细胞内走向细胞外：例如，双特异性抗体可通过桥接受体或免疫细胞，实现细胞外蛋白的选择性降解或免疫通路的精准调控。临床层面，已有十余款双抗获批，覆盖T细胞重定向与信号激活、双免疫检查点阻断等多个方向，显示出强劲的转化潜力。 图片来源：123RF 更进一步，研究人员也正在探索双功能分子被用于精准调控后翻译修饰，包括蛋白磷酸化、乙酰化、糖基化等；甚至可以改变特定蛋白的亚细胞定位，或实现转录激活，在更高层级上影响细胞命运。这意味着未来药物将不再只是“打开或关闭”单一靶点，而是通过多维调控实现对细胞功能的可编程重塑。 从分子胶到PROTAC，从天然产物到理性设计，诱导邻近疗法正重塑药物发现的范式。它不仅让“难以成药”的蛋白重回舞台，也为多层级生命调控提供了新的钥匙。随着结构生物学与化学生物学的深度融合，这一领域正从偶然发现走向可预测的理性创新，预示着精准药物新时代的加速到来。 参考资料： [1] King EA, Meyers M, Nomura DK. Induced proximity-based therapeutic modalities. Nat Rev Drug Discov. 2025 Oct 31. doi: 10.1038/s41573-025-01316-z. Epub ahead of print. PMID: 41174297. 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

BURLINGTON, Mass.--(BUSINESS WIRE)--PharmaEssentia USA Corporation, a subsidiary of PharmaEssentia Corporation (TWSE: 6446), a global biopharmaceutical innovator based in Taiwan leveraging deep expertise and proven scientific principles to deliver new biologics in hematology and oncology, today announced that positive results from its pivotal Phase 3 SURPASS-ET clinical trial (NCT04285086) have been published in The Lancet Haematology. The paper, titled “Ropeginterferon alfa-2b in hydroxyurea-intolerant or hydroxyurea-refractory essential thrombocythaemia (SURPASS ET): a multicentre, open-label, randomised, active-controlled, phase 3 study,” highlights the potential of ropeginterferon alfa-2b-njft as a new therapeutic option for patients with essential thrombocythemia (ET). ET is a chronic myeloproliferative neoplasm (MPN) characterized by uncontrolled platelet production and an elevated risk of blood clots, bleeding events and progression to more serious cancers. There have been no new treatments approved in the United States for ET since anagrelide in 1997, underscoring the need for new innovative therapies. SURPASS-ET compared ropeginterferon alfa-2b with anagrelide in patients with ET with leukocytosis who were resistant or intolerant to hydroxyurea. Data showed that ropeginterferon alfa-2b achieved statistically superior responses, with 43% of patients demonstrating durable responses at months 9 and 12 (as defined by modified ELN criteria) compared with 6% of those receiving anagrelide. Beyond the primary endpoint, ropeginterferon alfa-2b demonstrated more robust hematologic responses, greater symptom improvement, improved control of splenomegaly, fewer thromboembolic events and deeper molecular responses across key patient subgroups. Notably, treatment with ropeginterferon alfa-2b resulted in significant reductions in JAK2 V617F allele burden, an important indicator of potential disease-modifying activity in MPNs. The therapy was also well tolerated, with no major cardiac or neurological events and lower rates of significant adverse events and treatment discontinuations relative to anagrelide. “The SURPASS-ET data are impressive and demonstrate not only durable clinical and symptomatic benefits with ropeginterferon alfa-2b, but also reductions in JAK2 V617F allele burden—an important marker associated with potential disease modification,” said Ruben Mesa, MD, lead author of the publication, principal investigator of the SURPASS-ET trial and President of Advocate Health’s Cancer National Service Line, which includes Atrium Health Levine Cancer Institute and the Comprehensive Cancer Center at Atrium Health Wake Forest Baptist. “ET remains a challenging chronic disease, and patients who are resistant or intolerant to hydroxyurea have had few alternatives for sustained disease control. After nearly three decades without new therapeutic options, these findings represent a promising step forward for patients and clinicians.” “We are encouraged to see the SURPASS-ET results recognized in a leading peer-reviewed journal,” said Ko-Chung Lin, PhD, Founder and Chief Executive Officer of PharmaEssentia. “Ropeginterferon alfa-2b-njft has already reshaped the treatment landscape for polycythemia vera, and the findings from this study further reinforce its potential to benefit patients across the MPN spectrum. We look forward to advancing our regulatory efforts to bring this therapy to individuals living with ET, supporting the potential to expand our commercialization efforts in this new indication in 2026, pending FDA approval.” About PharmaEssentia PharmaEssentia USA Corporation, located in Burlington, Massachusetts, is a subsidiary of PharmaEssentia Corporation (TWSE: 6446). PharmaEssentia Corporation, headquartered in Taipei, Taiwan, is a global and rapidly growing biopharmaceutical innovator. Leveraging deep expertise and proven scientific principles, PharmaEssentia aims to deliver effective new biologics for challenging diseases in the areas of hematology, oncology, and immunology with one approved product and a diversifying pipeline. Founded in 2003 by a team of Taiwanese-American executives and renowned scientists from U.S. biotechnology and pharmaceutical companies, today PharmaEssentia is expanding its global presence with operations in the U.S., Japan, China, and Korea, along with a world-class biologics production facility in Taichung, Taiwan. For more information about PharmaEssentia USA, visit the website, LinkedIn or X (formerly Twitter). About Essential Thrombocythemia (ET) Essential thrombocythemia is a rare blood disorder and type of myeloproliferative neoplasm (MPN). It is characterized by the bone marrow overproducing platelets. Patients with ET are at an increased risk of blood clots, abnormal bleeding and enlarged spleens. ET is often caused by genetic mutations such as a JAK2 genetic mutation. About BESREMi® (ropeginterferon alfa-2b-njft) Ropeginterferon alfa-2b-njft is currently FDA-approved and marketed as BESREMi® for the treatment of adults with polycythemia vera (PV). The Company plans to seek a ropeginterferon alfa-2b-njft label expansion to include ET and has submitted a sBLA with the U.S. FDA. BESREMi® holds orphan drug designation in the United States for the treatment of polycythemia vera (PV) in adults. It has received regulatory approval in over 40 countries, including from the European Medicines Agency (2019), the U.S. Food and Drug Administration (2021), and the Pharmaceuticals and Medical Devices Agency in Japan (2023). The product was developed by PharmaEssentia. PharmaEssentia retains full global intellectual property rights across all indications. INDICATION BESREMi® is indicated for the treatment of adults with polycythemia vera. IMPORTANT SAFETY INFORMATION WARNING: RISK OF SERIOUS DISORDERS Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy. CONTRAINDICATIONS Existence of or history of severe depression, suicidal ideation, or suicide attempt Hypersensitivity to interferons or any inactive ingredients Moderate or severe hepatic impairment History or presence of active serious or untreated autoimmune disease History of transplantation and receiving immunosuppressant agents WARNINGS AND PRECAUTIONS Patients exhibiting the following events should be closely monitored and may require dose reduction or discontinuation of therapy: Depression and Suicide: Monitor closely for symptoms and need for treatment. Endocrine Toxicity: Discontinue if endocrine disorders occur that cannot be medically managed. Cardiovascular Toxicity: Avoid use in patients with severe, acute or unstable cardiovascular disease. Monitor patients with history of cardiovascular disorders more frequently. Decreased Peripheral Blood Counts: Perform blood counts at baseline, every 2 weeks during titration, and at least every 3-6 months during maintenance treatment. Hypersensitivity Reactions: Stop treatment and immediately manage reaction. Pancreatitis: Consider discontinuation if confirmed pancreatitis Colitis: Discontinue if signs or symptoms of colitis Pulmonary Toxicity: Discontinue if pulmonary infiltrates or pulmonary function impairment Ophthalmologic Toxicity: Advise patients to have eye examinations before and during treatment. Evaluate eye symptoms promptly and discontinue if new or worsening eye disorders. Hyperlipidemia: Monitor serum triglycerides before BESREMi® treatment and intermittently during therapy and manage when elevated. Hepatotoxicity: Monitor liver enzymes and hepatic function at baseline and during treatment. Reduce dose or discontinue depending on severity. Renal Toxicity: Monitor serum creatinine at baseline and during therapy. Discontinue if severe renal impairment develops. Dental and Periodontal Toxicity: Advise patients on good oral hygiene and to have regular dental examinations. Dermatologic Toxicity: Consider discontinuing if clinically significant dermatologic toxicity. Driving and Operating Machinery: Advise patients to avoid driving or using machinery if they experience dizziness, somnolence, or hallucination. Please see full Prescribing Information, including Boxed Warning.