ArticleThe Journal of clinical investigation2020
Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
36 citing papers in PubMed, 53 citations in OpenAlex.
- Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma.Annals of oncology : official journal of the European Society for Medical Oncology · 2024Trial
- The role of hypoxia-inducible factors in myocardial ischaemia-reperfusion injury and cardioprotection.Nature reviews. Cardiology · 2026Review
- SET1B Drives Sustained HIF Activity and Disease Progression in Clear-Cell Renal Cell Carcinoma.Cancer research · 2026Article
- The clinical landscape of HIF2α inhibitors in oncology.Nature reviews. Clinical oncology · 2026Review
- HIF inhibition: Current strategies and clinical challenges.Redox biology · 2026Review
- Exacerbated ATP transmission in the carotid body is linked to glomus cell expansion in spontaneously hypertensive rats.The Journal of physiology · 2026Article
- Targeting conserved domains of hypoxia-inducible factors for cancer therapy.The Journal of experimental medicine · 2026Article
- Review
- Targeting ecto-5'-nucleotidase (CD73) and cAMP alleviates carotid body hyperactivity and reduces blood pressure in chronically hypoxic rats.The Journal of physiology · 2026Article
- Belzutifan-Associated Hypoxia: A Review of the Novel Therapeutic, Proposed Mechanisms of Hypoxia, and Management Recommendations.International journal of molecular sciences · 2025Review
- Chronic cerebral hypoperfusion induces venous dysfunction via EPAS1 regulation in mice.Nature communications · 2025Article
- Translating physiology of the arterial chemoreflex into novel therapeutic interventions targeting carotid bodies in cardiometabolic disorders.The Journal of physiology · 2025Review
- Pharmacological targeting of BMAL1 modulates circadian and immune pathways.Nature chemical biology · 2025Article
- Cluster Headache and Hypoxia: Breathing New Life into an Old Theory, with Novel Implications.Neurology international · 2024Review
- Synchrotron X-ray imaging of soft biological tissues - principles, applications and future prospects.Journal of cell science · 2024Review
- Hif-2α programs oxygen chemosensitivity in chromaffin cells.The Journal of clinical investigation · 2024Article
- Genetic identification of medullary neurons underlying congenital hypoventilation.Science advances · 2024Article
- Deficiency of factor-inhibiting HIF creates a tumor-promoting immune microenvironment.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Targeting hypoxia-inducible factors: therapeutic opportunities and challenges.Nature reviews. Drug discovery · 2024Review
- Hypoxic Signaling Pathways in Carotid Body Tumors.Cancers · 2024Review
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 2 countries.
Funding
Abstract
Hypoxia-inducible factor (HIF) is strikingly upregulated in many types of cancer, and there is great interest in applying inhibitors of HIF as anticancer therapeutics. The most advanced of these are small molecules that target the HIF-2 isoform through binding the PAS-B domain of HIF-2α. These molecules are undergoing clinical trials with promising results in renal and other cancers where HIF-2 is considered to be driving growth. Nevertheless, a central question remains as to whether such inhibitors affect physiological responses to hypoxia at relevant doses. Here, we show that pharmacological HIF-2α inhibition with PT2385, at doses similar to those reported to inhibit tumor growth, rapidly impaired ventilatory responses to hypoxia, abrogating both ventilatory acclimatization and carotid body cell proliferative responses to sustained hypoxia. Mice carrying a HIF-2α PAS-B S305M mutation that disrupts PT2385 binding, but not dimerization with HIF-1β, did not respond to PT2385, indicating that these effects are on-target. Furthermore, the finding of a hypomorphic ventilatory phenotype in untreated HIF-2α S305M mutant mice suggests a function for the HIF-2α PAS-B domain beyond heterodimerization with HIF-1β. Although PT2385 was well tolerated, the findings indicate the need for caution in patients who are dependent on hypoxic ventilatory drive.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.