Daprodustat

编者按：2025年诺贝尔奖即将在下周揭晓。作为全球科学研究领域的至高荣誉之一，诺贝尔奖已走过一个多世纪，见证了无数推动人类文明进步的重大突破。从基础科学的前沿探索到造福患者的临床应用，许多获奖成果已成为现代医学的基石，催生出改变疾病治疗格局的创新疗法。在这些成就中，氧感知机制的发现是一座里程碑，不仅揭示了人类和动物生存所必需的关键通路，也催生了治疗贫血、癌症等疾病的创新疗法。本文将回顾氧感知通路的突破性研究如何走出实验室，转化为造福人类健康的现实成果。 维持供氧平衡的调控系统 众所周知，包括人类在内的绝大多数动物都离不开氧气。然而，我们对于氧气的需求必须保持微妙的平衡：缺氧会导致窒息，氧气过多又会引发中毒。为此，生物体演化出一系列精妙机制来维持氧气稳态。比如，红细胞能将氧气输送至组织深处，当氧气不足时，机体则会加速红细胞生成，以确保氧含量处于合理范围。 上世纪90年代，英国分子生物学家Peter Ratcliffe教授和美国遗传医学家Gregg Semenza教授率领的团队揭开了这一现象背后的机制。他们发现，名为缺氧诱导因子（HIF）的复合体可与基因调控序列结合，激活多种应对缺氧的基因表达，其中包括编码血管内皮生长因子（VEGF）和促红细胞生成素（EPO）的基因。这些蛋白能够刺激血管增生和红细胞生成，从而帮助机体获得更多氧气。 作为关键的调控蛋白，HIF在缺氧环境下启动基因表达，而在富氧环境中则会被迅速降解。那么，氧气是如何决定HIF的命运呢？答案出乎意料，竟隐藏在一个看似完全无关的研究中。 图片来源：123RF VHL与氧感知机制 让我们把话题转向William Kaelin教授。当时，他正在研究一种叫做希佩尔-林道综合征（VHL disease）的癌症综合征。他注意到，典型的VHL肿瘤往往伴随新生血管异常增生，并伴有VEGF和EPO水平升高。因此他自然而然地想到，缺氧通路是否在这种疾病中发挥作用。 1996年，Kaelin教授团队发表的研究显示，缺乏正常VHL基因的细胞即使处于富氧环境，也会表现出缺氧的生理反应，而补充正常功能的VHL蛋白则能逆转这一现象。1999年，Ratcliffe教授团队证明了缺乏VHL蛋白的细胞无法降解HIF，将VHL的功能与HIF联系起来。在这一研究的启发下，Kaelin教授的团队和其他研究人员一起澄清了VHL调控HIF的信号通路。原来HIF复合体的重要组成部分HIF-1α与VHL的结合需要氧原子的参与：在富氧情况下，HIF-1α的羟基化让它能够与VHL结合，被VHL介导的泛素-蛋白酶体系统降解，而在缺氧情况下，羟基化无法进行，HIF-1α因而逃脱降解。 2019年，诺贝尔委员会宣布，将当年的诺贝尔生理学或医学奖授予Peter Ratcliffe、Gregg Semenza和William Kaelin教授，表彰他们在揭示氧感知信号通路方面的突出贡献。诺贝尔委员会同时在新闻稿中指出，他们的研究不但揭示了生命中不可或缺的适应性机制，而且为开发治疗贫血、癌症等疾病的创新药物铺平了道路。 ▲William Kaelin教授（左）、Peter Ratcliffe教授（中）、以及Gregg Semenza教授（右）（图片来源：NobelPrize.org） 从科学突破到抗癌创新疗法 2002-2003年，Kaelin教授团队的实验证明，在缺乏VHL的肾癌细胞中，抑制HIF功能可显著阻止肿瘤的生长，确立了HIF与肿瘤生长之间的因果关系。进一步研究显示，HIF家族中除了最初发现的HIF-1，还有一个关键成员HIF-2。HIF-2α不仅能与HIF-1β结合并激活包括VEGF在内的促癌基因，还可上调癌基因MYC的水平。因此，HIF-2α被确立为一个理想的抗癌靶点。 然而，HIF-2是一个调节基因表达的转录因子，与蛋白激酶不同，转录因子通过与DNA序列结合产生活性，它并没有一个理想的活性“口袋”被小分子抑制剂靶向。因此，当时很多转录因子被认为是“不可成药”的靶点。 得克萨斯大学西南医学中心的Richard Bruick和Kevin Gardner博士率领的团队在靶向HIF-2方面做出了突破。他们发现HIF-2α蛋白上面存在一个别构“口袋”，与这个“口袋”结合的小分子能够影响HIF-2α蛋白的构象，进而抑制HIF-2的活性。 基于这一研究而诞生的Peloton Therapeutics公司通过高通量筛选，发现了候选小分子疗法PT2385和PT2977，并且把它们推进到临床开发阶段。在2019年，默沙东（MSD）斥资约22亿美元收购了Peloton公司及其核心在研疗法PT2977，并继续推动它在晚期肾细胞癌（RCC）和透明细胞肾癌方面的临床试验。这款创新疗法就是后来的belzutifan。 ▲Belzutifan的作用机制（图片来源：参考资料[4]） 2021年8月，美国FDA批准Welireg（belzutifan）上市，用于治疗VHL疾病相关癌症，包括肾细胞癌、中枢神经系统血管母细胞瘤或胰腺神经内分泌肿瘤（pNET）。Welireg是首个获批上市的HIF-2α抑制剂。在2023年，FDA批准Welireg扩展适应症，用于治疗晚期RCC患者，这些患者接受PD-1/PD-L1抑制剂和血管内皮生长因子酪氨酸激酶抑制剂（VEGF-TKI）治疗后发生疾病进展。 催生多款创新贫血疗法 在HIF-2α抑制剂取得成功的同时，多家生物医药公司也在探索通过提高HIF蛋白的水平来调节人体对缺氧状态的反应，治疗贫血。因为HIF复合体能够调控与缺氧状态相关的多个生理过程，包括血红细胞的生成和铁元素的运输等等，因此成为贫血治疗的重要突破口。 HIF脯氨酰羟化酶（HIF-PH）通过对HIF的修饰，导致HIF被蛋白酶体降解，从而降低机体内的HIF水平。它是细胞在富氧环境下降低HIF水平的重要调控机制。HIF-PH抑制剂通过抑制HIF脯氨酰羟化酶的作用，提升HIF活性，从而起到缓解贫血的效果。 ▲HIF脯氨酰羟化酶抑制剂的作用机制（图片来源：参考资料[5]） 目前，多款HIF-PH抑制剂已经获得批准上市，例如用于治疗因慢性肾病引起贫血的roxadustat、daprodustat、vadadustat、molidustat和enarodustat。不仅如此，针对氧感知通路的药物研发仍在快速推进，据统计，20多款靶向HIF信号通路的在研药物已经进入临床阶段。药明康德多年以来通过其一体化、端到端的CRDMO平台，为包括氧感知通路靶向药物在内的广泛新药研发提供从药物研究（R）、开发（D）到商业化生产（M）各个阶段的支持，助力全球合作伙伴加速突破性疗法面世，早日造福病患。 结语 从2019年氧感知通路研究斩获诺贝尔奖，到如今多款靶向HIF信号通路的药物相继问世，这段历程展现了科学与产业界携手推动创新的力量。药明康德也有幸见证这一旅程，并为创新者提供赋能。展望未来，药明康德将继续依托独特的一体化、端到端CRDMO平台，助力合作伙伴将更多科学突破转化为新药好药，造福全球病患。 Tackling the "Undruggable": Nobel Prize Research Leads to a "First-in-Class" Anti-Cancer Therapy The 2025 Nobel Prize will soon be announced. As one of the most prestigious honors in global science, the Nobel Prize has recognized groundbreaking achievements for more than a century, driving advances that have shaped human civilization. From the frontiers of basic research to transformative clinical applications, many discoveries have become cornerstones of modern medicine, giving rise to therapies that reshaped the treatment landscape. Among these milestones, the discovery of oxygen sensing mechanisms stands out. This breakthrough not only revealed a pathway essential to human and animal survival but also paved the way for innovative therapies targeting anemia, cancer, and other diseases. This article looks back at how research into oxygen sensing evolved from laboratory findings into real-world medical breakthroughs. A System for Maintaining Oxygen Balance Oxygen is essential for nearly all animals, including humans. Yet oxygen demand must remain delicately balanced: too little causes suffocation, while too much can lead to toxicity. To maintain this balance, organisms evolved sophisticated mechanisms. Red blood cells, for instance, deliver oxygen deep into tissues, and when oxygen becomes scarce, the body increases red blood cell production to stabilize oxygen levels. In the 1990s, Sir Peter Ratcliffe in the UK and Dr. Gregg Semenza in the US unraveled the molecular basis of this process. They discovered that hypoxia-inducible factor (HIF), a protein complex, binds to regulatory DNA sequences and activates genes responsive to low oxygen. These include genes encoding vascular endothelial growth factor (VEGF) and erythropoietin (EPO), which drive angiogenesis and red blood cell formation, helping the body adapt to hypoxic conditions. As a central regulator, HIF activates gene expression under low oxygen but is degraded when oxygen is abundant. The question remained: how exactly does oxygen determine HIF’s fate? The surprising answer emerged from research in a seemingly unrelated area. VHL and the Oxygen Sensing Mechanism The focus then shifted to Dr. William Kaelin, who was studying von Hippel–Lindau (VHL) disease, a cancer syndrome. He observed that tumors in these patients often featured abnormal angiogenesis along with elevated VEGF and EPO levels. This led him to suspect that the hypoxia pathway might play a role. In 1996, Kaelin’s team demonstrated that cells lacking functional VHL genes displayed hypoxia-like responses even under normal oxygen conditions, while restoring VHL protein reversed the effect. Three years later, Ratcliffe’s group confirmed that VHL-deficient cells could not degrade HIF, firmly linking VHL to HIF regulation. Subsequent studies revealed that degradation of HIF-1α requires oxygen-dependent hydroxylation, which enables binding to VHL and subsequent proteasomal destruction. Under hypoxia, this hydroxylation cannot occur, allowing HIF-1α to accumulate. In recognition of these discoveries, the 2019 Nobel Prize in Physiology or Medicine was awarded to Drs. Ratcliffe, Semenza, and Kaelin. The Nobel Committee emphasized that their work not only uncovered a fundamental adaptive mechanism of life but also laid the foundation for therapies against anemia, cancer, and other diseases. From Scientific Breakthrough to Cancer Therapy Building on this foundation, Kaelin’s team showed in 2002–2003 that inhibiting HIF in VHL-deficient renal cancer cells halted tumor growth. These findings established a causal link between HIF activity and cancer progression. Further research highlighted HIF-2, a critical family member distinct from HIF-1. HIF-2α forms a complex with HIF-1β to activate oncogenic pathways such as VEGF, and it also upregulates MYC, reinforcing its role as a compelling cancer target. Yet drug development faced a major hurdle: as a transcription factor, HIF-2 lacked the well-defined binding “pockets” typical of kinase targets, leading many to dismiss it as “undruggable.” A breakthrough came from Drs. Richard Bruick and Kevin Gardner at the University of Texas Southwestern Medical Center, who discovered an allosteric pocket on HIF-2α. Small molecules binding to this site altered the protein’s conformation and inhibited its activity. Peloton Therapeutics built on this discovery, using high-throughput screening to identify candidate therapies PT2385 and PT2977, advancing both into clinical development. In 2019, Merck (MSD outside the US and Canada) acquired Peloton for $2.2 billion and continued advancing PT2977 (later known as belzutifan) in renal cell carcinoma (RCC) and clear cell RCC. In August 2021, the US FDA approved Welireg (belzutifan) for VHL disease-associated cancers, including RCC, CNS hemangioblastomas, and pancreatic neuroendocrine tumors (pNET). This marked the first approval of an HIF-2α inhibitor. In 2023, the FDA expanded Welireg’s indication to advanced RCC patients whose disease had progressed after treatment with PD-1/PD-L1 and VEGF receptor inhibitors. Expanding into Innovative Anemia Therapies While HIF-2α inhibitors broke new ground in oncology, other companies explored the opposite approach—enhancing HIF activity to treat anemia. Because HIF regulates red blood cell production and iron metabolism, stabilizing HIF became a promising therapeutic strategy. HIF prolyl hydroxylase (HIF-PH) normally hydroxylates HIF, marking it for proteasomal degradation. Inhibiting this enzyme stabilizes HIF, increasing its activity and alleviating anemia. Several HIF-PH inhibitors have now been approved to treat anemia in chronic kidney disease, including roxadustat, daprodustat, vadadustat, molidustat, and enarodustat. Meanwhile, the field of oxygen sensing therapeutics continues to expand, with more than 20 HIF pathway-targeted candidates in clinical development. As a trusted partner to global innovators, WuXi AppTec plays a pivotal role in the development of novel therapies, including those targeting the HIF pathway, through its fully integrated CRDMO model. Providing seamless support across the entire drug development spectrum, enabling faster, more cost-effective progress from discovery to commercialization. From the Nobel Prize-winning discovery of oxygen sensing in 2019 to today’s approved therapies targeting the HIF pathway, this journey illustrates how basic science can transform into life-changing medicines. WuXi AppTec is proud to have supported this progress and will continue leveraging its integrated, end-to-end CRDMO platform to help partners translate scientific advances into breakthrough therapies, ultimately benefiting patients worldwide. 参考资料： [1] How Researchers Harnessed the Momentum of Discovery to Create a New Kidney Cancer Drug. Retrieved September 17, 2025, from https://www.dana-farber.org/newsroom/features/belzutifan-journey [2] The Nobel Prize in Physiology or Medicine 2019, Retrieved October 7, 2019, from https://www.nobelprize.org/prizes/medicine/2019/summary/ [3] 2016 Albert Lasker Basic Medical Research Award: Oxygen sensing – an essential process for survival, Retrieved October 7, 2019, from http://www.laskerfoundation.org/awards/show/oxygen-sensing-essential-process-survival/ [4] Choi, et al. (2023) Belzutifan (MK-6482): Biology and Clinical Development in Solid Tumors. Curr Oncol Rep, https://doi.org/10.1007/s11912-022-01354-5 [5] Beck et al., (2018). Discovery of Molidustat (BAY 85-3934): A Small-Molecule Oral HIF-Prolyl Hydroxylase (HIF-PH) Inhibitor for the Treatment of Renal Anemia. ChemMedChem, DOI: 10.1002/cmdc.201700783 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