同行致遠 | 攻克“不可成藥”靶點，諾獎研究帶來“first-in-class”抗癌藥物 | Bilingual

編者按：2025年諾貝爾獎即將在下周揭曉。作為全球科學研究領域的至高榮譽之一，諾貝爾獎已走過一個多世紀，見證了無數推動人類文明進步的重大突破。從基礎科學的前沿探索到造福患者的臨床應用，許多獲獎成果已成為現代醫學的基石，催生出改變疾病治療格局的創新療法。在這些成就中，氧感知機制的發現是一座里程碑，不僅揭示了人類和動物生存所必需的關鍵通路，也催生了治療貧血、癌癥等疾病的創新療法。本文將回顧氧感知通路的突破性研究如何走出實驗室，轉化為造福人類健康的現實成果。

維持供氧平衡的調控系統

眾所周知，包括人類在內的絕大多數動物都離不開氧氣。然而，我們對于氧氣的需求必須保持微妙的平衡：缺氧會導致窒息，氧氣過多又會引發中毒。為此，生物體演化出一系列精妙機制來維持氧氣穩態。比如，紅細胞能將氧氣輸送至組織深處，當氧氣不足時，機體則會加速紅細胞生成，以確保氧含量處于合理范圍。

上世紀90年代，英國分子生物學家Peter Ratcliffe教授和美國遺傳醫學家Gregg Semenza教授率領的團隊揭開了這一現象背后的機制。他們發現，名為缺氧誘導因子（HIF）的復合體可與基因調控序列結合，激活多種應對缺氧的基因表達，其中包括編碼血管內皮生長因子（VEGF）和促紅細胞生成素（EPO）的基因。這些蛋白能夠刺激血管增生和紅細胞生成，從而幫助機體獲得更多氧氣。

作為關鍵的調控蛋白，HIF在缺氧環境下啟動基因表達，而在富氧環境中則會被迅速降解。那么，氧氣是如何決定HIF的命運呢？答案出乎意料，竟隱藏在一個看似完全無關的研究中。

圖片來源：123RF

VHL與氧感知機制

讓我們把話題轉向William Kaelin教授。當時，他正在研究一種叫做希佩爾-林道綜合征（VHL disease）的癌癥綜合征。他注意到，典型的VHL腫瘤往往伴隨新生血管異常增生，并伴有VEGF和EPO水平升高。因此他自然而然地想到，缺氧通路是否在這種疾病中發揮作用。

1996年，Kaelin教授團隊發表的研究顯示，缺乏正常

VHL

2019年，諾貝爾委員會宣布，將當年的諾貝爾生理學或醫學獎授予Peter Ratcliffe、Gregg Semenza和William Kaelin教授，表彰他們在揭示氧感知信號通路方面的突出貢獻。諾貝爾委員會同時在新聞稿中指出，他們的研究不但揭示了生命中不可或缺的適應性機制，而且為開發治療貧血、癌癥等疾病的創新藥物鋪平了道路。

▲William Kaelin教授（左）、Peter Ratcliffe教授（中）、以及Gregg Semenza教授（右）（圖片來源：NobelPrize.org）

從科學突破到抗癌創新療法

2002-2003年，Kaelin教授團隊的實驗證明，在缺乏VHL的腎癌細胞中，抑制HIF功能可顯著阻止腫瘤的生長，確立了HIF與腫瘤生長之間的因果關系。進一步研究顯示，HIF家族中除了最初發現的HIF-1，還有一個關鍵成員HIF-2。HIF-2α不僅能與HIF-1β結合并激活包括

VEGF

MYC

然而，HIF-2是一個調節基因表達的轉錄因子，與蛋白激酶不同，轉錄因子通過與DNA序列結合產生活性，它并沒有一個理想的活性“口袋”被小分子抑制劑靶向。因此，當時很多轉錄因子被認為是“不可成藥”的靶點。

得克薩斯大學西南醫學中心的Richard Bruick和Kevin Gardner博士率領的團隊在靶向HIF-2方面做出了突破。他們發現HIF-2α蛋白上面存在一個別構“口袋”，與這個“口袋”結合的小分子能夠影響HIF-2α蛋白的構象，進而抑制HIF-2的活性。

基于這一研究而誕生的Peloton Therapeutics公司通過高通量篩選，發現了候選小分子療法PT2385和PT2977，并且把它們推進到臨床開發階段。在2019年，默沙東（MSD）斥資約22億美元收購了Peloton公司及其核心在研療法PT2977，并繼續推動它在晚期腎細胞癌（RCC）和透明細胞腎癌方面的臨床試驗。這款創新療法就是后來的belzutifan。

▲Belzutifan的作用機制（圖片來源：參考資料[4]）

2021年8月，美國FDA批準Welireg（belzutifan）上市，用于治療VHL疾病相關癌癥，包括腎細胞癌、中樞神經系統血管母細胞瘤或胰腺神經內分泌腫瘤（pNET）。Welireg是首個獲批上市的HIF-2α抑制劑。在2023年，FDA批準Welireg擴展適應癥，用于治療晚期RCC患者，這些患者接受PD-1/PD-L1抑制劑和血管內皮生長因子酪氨酸激酶抑制劑（VEGF-TKI）治療后發生疾病進展。

催生多款創新貧血療法

在HIF-2α抑制劑取得成功的同時，多家生物醫藥公司也在探索通過提高HIF蛋白的水平來調節人體對缺氧狀態的反應，治療貧血。因為HIF復合體能夠調控與缺氧狀態相關的多個生理過程，包括血紅細胞的生成和鐵元素的運輸等等，因此成為貧血治療的重要突破口。

HIF脯氨酰羥化酶（HIF-PH）通過對HIF的修飾，導致HIF被蛋白酶體降解，從而降低機體內的HIF水平。它是細胞在富氧環境下降低HIF水平的重要調控機制。HIF-PH抑制劑通過抑制HIF脯氨酰羥化酶的作用，提升HIF活性，從而起到緩解貧血的效果。

▲HIF脯氨酰羥化酶抑制劑的作用機制（圖片來源：參考資料[5]）

目前，多款HIF-PH抑制劑已經獲得批準上市，例如用于治療因慢性腎病引起貧血的roxadustat、daprodustat、vadadustat、molidustat和enarodustat。不僅如此，針對氧感知通路的藥物研發仍在快速推進，據統計，20多款靶向HIF信號通路的在研藥物已經進入臨床階段。藥明康德多年以來通過其一體化、端到端的CRDMO平臺，為包括氧感知通路靶向藥物在內的廣泛新藥研發提供從藥物研究（R）、開發（D）到商業化生產（M）各個階段的支持，助力全球合作伙伴加速突破性療法面世，早日造福病患。

結語

從2019年氧感知通路研究斬獲諾貝爾獎，到如今多款靶向HIF信號通路的藥物相繼問世，這段歷程展現了科學與產業界攜手推動創新的力量。藥明康德也有幸見證這一旅程，并為創新者提供賦能。展望未來，藥明康德將繼續依托獨特的一體化、端到端CRDMO平臺，助力合作伙伴將更多科學突破轉化為新藥好藥，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

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

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.

參考資料：

[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

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