MK-3795 / Merck (MSD) - LARVOL DELTA

UBE2M Deficiency in Alveolar Macrophages Promotes Emphysema through HIF-2α/MMP12 Axis (ERS 2026) - "The HIF-2α inhibitor PT2385 attenuated Mmp12 upregulation, and double knockout of Ube2m and Epas1 significantly ameliorated emphysema development. Our study identifies UBE2M as a critical guardian against emphysema by targeting HIF-2α for degradation, thereby suppressing MMP12 expression. The UBE2M-HIF-2α-MMP12 axis represents a novel and specific pathogenic pathway in COPD, offering promising therapeutic targets."

Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • EPAS1 • UBE2M

UBE2M deficiency in alveolar macrophages promotes emphysema through HIF-2α/MMP12 axis. (PubMed, Chin Med J Pulm Crit Care Med) - "The HIF-2α inhibitor PT2385 attenuated Mmp12 upregulation, and double knockout of Ube2m and Epas1 (UBE2M-EPAS1-DKO) significantly ameliorated emphysema development. Our study identifies UBE2M as a critical protector against emphysema by promoting HIF-2α degradation, thereby suppressing MMP12 expression. The UBE2M-HIF-2α-MMP12 axis represents a novel and specific pathogenic pathway in COPD, offering promising therapeutic targets."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • Targeted Protein Degradation • EPAS1 • UBE2M

IL-1β/EPAS1-Associated Ferroptotic Stress Impairs Skeletal Stem/Progenitor Cell Function in Inflammation-Associated Fracture Nonunion. (PubMed, Curr Issues Mol Biol) - "Pharmacological inhibition of EPAS1 with PT2385 attenuated IL-1β-induced ferroptotic stress and restored SSPC differentiation in vitro, while also improving IL-1β-impaired fracture repair in vivo. Mendelian randomization analysis provided additional genetic evidence supporting potential links among IL-1β, EPAS1, and human nonunion risk. Together, these findings suggest that an IL-1β/EPAS1-associated ferroptotic program contributes to SSPC dysfunction during inflammation-associated fracture nonunion and may represent a potential targetable mechanism for improving impaired bone repair."

Journal • Inflammation • Musculoskeletal Diseases • Orthopedics • ACSL4 • EPAS1 • IL1B

Codelivery Material System of Polymer Microfiber Structures for Synergistic Localized Therapy of Glioblastoma. (PubMed, ACS Biomater Sci Eng) - "We report on the synergistic effect of the FDA-approved anti-GBM drug (temozolomide) and inhibitors (acriflavine, PT2385) of hypoxia-inducible factors (HIFs) embedded into coaxial fiber membranes (NanoMesh). In vitro cytotoxicity has been evaluated for various glioma cell lines, and synergistic drug combinations have been identified. Preliminary animal studies with the three-drug-loaded NanoMesh indicate a significant improvement of median survival of >50 days and long-term (>120 days) survival rate of 40%, indicating the potential of this material platform as a translatable local GBM therapy."

Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor

Ischemia-free liver transplantation alleviates liver transplant injury caused by CD69+CD103-CD8+T cells by regulating HIF-2α expression. (PubMed, J Immunol) - "PT-2385 was administered to inhibit HIF-2α, and 100 µg of anti-mouse CD8α monoclonal antibody was injected to deplete CD8+ T cells...Under HIF-2α stimulation, CD69+CD103-CD8+ T cells exacerbate organ and tissue injury through TNF-related signaling. In IFLT, the absence of significant pathway upregulation suggests effective prevention of IRI."

Journal • Cardiovascular • Hepatology • Liver Failure • Reperfusion Injury • Transplantation • CD69 • CD8 • EPAS1 • ITGAE

Targeting conserved domains of hypoxia-inducible factors for cancer therapy. (PubMed, J Exp Med) - "Compared with the HIF-2-selective inhibitors belzutifan and PT2385, dual HIF-1/2 inhibitor 1.21S9N showed superior activity against breast and colorectal cancer models, respectively. PT2385 caused breathing abnormalities, whereas 1.21S9N did not. The drugs are orally bioavailable, and no safety concerns were identified even after extended or supratherapeutic dosing."

Journal • Breast Cancer • Colorectal Cancer • Melanoma • Oncology • Prostate Cancer • Solid Tumor • EPAS1 • HIF1A

Broad and synergistic anti-tumor effects of small-molecule dual HIF-1/2 inhibitors in combination with immune checkpoint inhibitors (AACR 2025) - "This study demonstrates the anti-tumor effects of dual HIF-1/2 inhibitors and their ability to modulate the tumor immune cell microenvironment, resulting in sustained tumor regression when added to immunotherapy. The promising outcomes of this study warrant further exploration of these inhibitors as potential cancer treatment modalities."

Checkpoint inhibition • Combination therapy • IO biomarker • Late-breaking abstract • Colorectal Cancer • Genito-urinary Cancer • Melanoma • Oncology • Prostate Cancer • Solid Tumor • EPAS1 • HIF1A

Exploring drivers of variability in patient tumor responses to HIF-2α inhibitor using the Xsphera patient-derived organotypic tumor spheroid (PDOTS) platform (AACR 2025) - "PDOTS from each patient tumor were treated with the HIF-2α inhibitors PT2977 (7.5-750 ng/mL) and PT2385 (50-5000 ng/mL), or vehicle control. Xsphera's PDOTS platform effectively mirrors the clinical response rates to HIF-2α inhibitors, offering actionable insights into tumor variability and resistance mechanisms. By combining cytotoxicity, immune profiling, and transcriptomic analyses, the PDOTS platform provides a robust predictive and exploratory tool for oncology drug development. These findings underscore the utility of this platform in tailoring therapeutic strategies for ccRCC and other cancer types."

Clinical • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD163 • EPAS1 • LILRB4

Targeting HIF-2α in Colorectal Cancer Reveals a Cholesterol Biosynthesis-Dependent Ferroptotic Vulnerability. (PubMed, bioRxiv) - "Targeting this pathway with clinically approved statins (atorvastatin, pitavastatin, simvastatin) synergized with PT2385 to suppress CRC cell growth, reduce colony formation, and enhance cell death...These effects are fully reversed by the ferroptosis inhibitor liproxstatin-1...In vivo, co-administration of PT2385 and atorvastatin significantly reduced tumor growth and increased ferroptotic cell death in xenografts, confirming the mechanistic link. Collectively, these findings uncover a metabolic vulnerability of CRC to dual HIF-2α and cholesterol biosynthesis inhibition, supporting a clinically actionable strategy that leverages safe, FDA-approved statins to potentiate HIF-2α-targeted therapy."

Journal • Colorectal Cancer • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1

HIF-2α expression is controlled by the progesterone receptor and regulates hCG-induced gene expression in granulosa cells during ovulation in mice. (PubMed, Mol Cell Endocrinol) - "PGR activation in response to hormonal stimulation induced expression of a HIF reporter system in primary human granulosa cells, with HIF-2 inhibition with the small molecule PT-2385 confirming a HIF-2 contribution to this response...In particular, inflammatory gene expression was dysregulated and a cohort of gonadotrophin-dependent genes, including Pgr, were elevated, suggesting impaired downregulation post-ovulation. These findings provide an important insight into regulation of the hypoxia inducible transcription factors during ovulation and how targeting HIF-2α may be of benefit in future fertility treatments."

Journal • Preclinical • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • EPAS1 • HIF1A • PGR

Targeting HIF-2α in renal cell carcinoma: Expanding upon belzutifan. (PubMed, Cancer) - "By expanding upon the foundation established by belzutifan, the field is poised for further therapeutic advances."

First-in-human • Journal • Review • Clear Cell Renal Cell Carcinoma • Developmental Disorders • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1 • VHL

Endothelial HIF2a signalling modulates hypoxia driven myeloid cell migration into the lung (BTS WM 2025) - "The co-culture of PT2385 (HIF2a inhibitor) with hPAEC exposed to hypoxia significantly reduced the expression of leukocyte adhesion molecules and chemokines. Conclusion Our data support pre-clinical studies in pulmonary hypertension which identified that drug intervention with a HIF2a specific inhibitor significantly reduced the migration of both monocytes and neutrophils into the lung. Further investigations are required to fully elucidate the role of HIF2a in leukocyte/endothelial transmigration and understand the potential beneficial effect of inhibiting HIF2a signalling in other neutrophil-driven pulmonary diseases."

Cardiovascular • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • CXCR4 • EPAS1 • FLT1 • HIF1A

Iron Deficiency Impairs Muscle Stem Cell Proliferation and Skeletal Muscle Regeneration via HIF-2α Stabilization. (PubMed, J Cachexia Sarcopenia Muscle) - "Iron deficiency impairs skeletal muscle regeneration by stabilizing HIF-2α in MuSC, inducing Rb1 RNA expression, and repressing E2F-dependent proliferation. Transient HIF-2α inhibition rescues MuSC proliferation and muscle repair under iron-deficient conditions, highlighting HIF-2α as a potential therapeutic target to counteract sarcopenia in aging and chronic diseases."

Journal • Eye Cancer • Hematological Disorders • Oncology • Retinal Disorders • Sarcopenia • Solid Tumor • EPAS1 • RB1

The novel hydrogen-PT2385-silncARSR nanocomplex impairs tumor angiogenesis and mitochondrial activity in sunitinib-resistant renal cancer. (PubMed, Mater Today Bio) - "Moreover, the combination of H2, silncARSR and PT2385 exerts significantly potentiated efficacy in modulating apoptosis-related protein expression and ultimately enhancing cancer cell mitochondrial apoptosis. The demonstrated high therapeutic efficacy and great biocompatibility of this Hydrogen-PT2385-silncARSR nanocomplex underscore the clinical translation potential for overcoming ccRCC sunitinib resistance."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1

Low Wall Shear Stress Promotes Atheroma via Arterial Iron Accumulation. (PubMed, Arterioscler Thromb Vasc Biol) - "The use of HIF inhibitors, PX-478 and PT-2385, was able to suppress the exacerbation of atherosclerosis in Apoe-/- mice caused by the endothelial cell-specific knockout of IRP2. Our results indicate that low WSS-induced endothelial cell iron metabolism abnormalities, by inducing arterial wall iron accumulation and abnormal expression of iron metabolism-related proteins, promote the occurrence and development of atherosclerosis. The use of iron chelators can alleviate the onset and progression of low WSS-induced atherosclerosis."

Journal • Atherosclerosis • Cardiovascular • Inflammation • APOE

Hypoxia-inducible factor 2α overexpression in podocytes ameliorates lipid metabolism disorders in diabetic kidney disease by inhibiting S1P. (PubMed, Ren Fail) - "In vivo, the effect of HIF-2α on lipid metabolism disorders in db/db mice was investigated using the HIF-2α inhibitor PT-2385. Furthermore, we found that FG-4592, a HIF prolyl hydroxylase inhibitor, reduced the total cholesterol level in DKD by activating HIF-2α, thereby protecting against DKD. HIF-2α ameliorated lipid metabolism disorders and podocyte damage in DKD by downregulating S1P, providing a novel insight for HIF-2α against DKD."

Journal • Diabetes • Diabetic Nephropathy • Dyslipidemia • Metabolic Disorders • Nephrology • Renal Disease • EPAS1 • SPHK1

Renal surgery following HIF-2α antagonist therapy: Surgical indications, outcomes and growth kinetics. (PubMed, Urol Oncol) - "Renal surgery after or during exposure to a HIF-2α antagonist is safe and feasible, with rates of both transfusions and complications commensurate with the reported literature from standard renal surgery. GRs of index renal tumors that eventually needed surgical intervention did not show a significant difference before, during, and after therapy. Tumors exhibiting a positive GR on drug may represent the indication that drives early surgical intervention prior to the tumor reaching the 3 cm threshold. A median washout time of 10 days from last dose of HIF-2α antagonist to surgery was safe and well tolerated."

Journal • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1

Downregulation of Protein S by hypoxia-inducible factor ?: is it HIF-1? or HIF-2? or both? (ISTH 2025) - "The cells were then treated with either 30 µM CAY10585 or with 30 µM PT-2385 to inhibit accumulation of HIF-1α or DNA binding of HIF-2α, respectively...2B). Table or Figure Upload"

Cardiovascular • Hematological Disorders • Thrombosis • EPAS1 • HIF1A • PROS1

HIF2 Activation Derails Alveolar Differentiation Through Metabolic, Biosynthetic, and Transcriptional Changes (ATS 2025) - "HIF-form biased activation was generated with Roxadustat, a prolyl-hydroxylase inhibitor to activate HIF-driven signaling, along with PT-2385 (HIF2 inhibitor) or M1002 (HIF2 allosteric activator). Persistent HIF2 activation in the alveolar epithelium prevents maturation and terminal differentiation through suppression of essential AT2 biosynthetic components and metabolic machinery, which results in disease-relevant changes in cellular identity and function. This constellation of findings points toward HIF2 inhibition as a novel therapeutic target to enhance alveolar repair in the treatment of fibrotic lung diseases."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • EPAS1 • KRT17 • KRT5 • SFTPC • VIM

Manganese-Doped Nanoparticles with Hypoxia-Inducible Factor 2α Inhibitor That Elicit Innate Immune Responses against von Hippel-Lindau Protein-Deficient Tumors. (PubMed, ACS Nano) - "In addressing the treatment of pVHL-deficient tumors, hypoxia-inducible factor 2α (HIF-2α) has risen as a promising therapeutic target, culminating in the development of specific inhibitors like PT2385 and its analogues...Additionally, the safety profile of PMMF showed minimal systemic post-treatment cytotoxicity. In summary, our findings position PMMF as a promising platform for treating tumors with pVHL deficiency and underscore the therapeutic potential of metalloimmunotherapy."

Journal • Genito-urinary Cancer • Melanoma • Oncology • Solid Tumor • Von Hippel-Lindau Syndrome • CD8 • CGAS • EPAS1 • STING

Chronic intermittent hypoxia alleviates alcohol-related liver injury via downregulation of hepatic hypoxia-inducible factor-2α. (PubMed, Am J Physiol Gastrointest Liver Physiol) - "The above results provide important, new evidence that re-conceptualizes the role of alcohol-enhanced OSA in ALD progression. Moreover, these findings can serve as the foundation for the development of HIF-2α inhibitors for use in the prevention and treatment of ALD."

Journal • Hepatology • Inflammation • Liver Failure • Metabolic Disorders • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder • EPAS1

Role of Hypoxia-Inducible Factors in Respiratory Syncytial Virus Infection-Associated Lung Disease. (PubMed, Int J Mol Sci) - "This study aimed to characterize the disease-modulating properties and antiviral potential of HIF-1α (PX478) and HIF-2α PT2385 inhibitors in RSV-infected BALB/c mice. The analysis of lung cells found significant modification in the T-cell compartment that correlated with changes in lung pathology and viral titers for each HIF inhibitor. This study underscores the differential roles of HIF proteins in RSV infection and highlights the need for further characterization of compounds currently in use or under therapeutic consideration."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • EPAS1 • HIF1A

High altitude renal syndrome: four elements or one source? (PubMed, Ren Fail) - "Carbonic anhydrase inhibitors (e.g., acetazolamide) reduce hematocrit and improve oxygen saturation, but newer agents like methazolamide and dichlorphenamide offer equivalent efficacy with fewer side effects (e.g., reduced central nervous system toxicity). Additional interventions include calcium channel blockers (nifedipine), urate-lowering drugs, and experimental therapies such as HIF-2α inhibitors (PT2385) and endothelin receptor antagonists (matitan). This analysis underscores HAPC as the primary etiology of HARS, advocating revised diagnostic criteria and treatment prioritization."

Journal • Review • Cardiovascular • Hematological Disorders • Hypertension • Nephrology • Renal Disease • EPAS1

Targeting HIF-2α in glioblastoma reshapes the immune infiltrate and enhances response to immune checkpoint blockade. (PubMed, Cell Mol Life Sci) - "Here, we investigate HIF-2α and the use of the HIF-2α inhibitor PT2385 to modulate the TME in the immunocompetent GL261 mouse GBM model...Our results show that targeting HIF-2α can switch an immunosuppressive TME towards one that favors a robust and sustained response to ICB based immunotherapy. These findings establish that clinically relevant HIF-2α inhibitors should be explored not only in malignancies with defects in the HIF-2α axis, but also in those exhibiting an immunosuppressive TME that limits immunotherapy responsiveness."

Checkpoint inhibition • IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • EPAS1 • HAVCR2

Hypoxia-inducible factor 2α mediates nonesterified fatty acids and hypoxia-induced lipid accumulation in bovine hepatocytes. (PubMed, J Dairy Sci) - "Meanwhile, normal or NEFA-treated hepatocytes were cocultured with or without PT2385, a specific HIF-2α inhibitor, showing that hypoxia promoted steatosis through HIF-2α...Overall, these data suggest that NEFA-induced hepatic hypoxia significantly contributes to the progression of hepatic steatosis which in turn, intensifies hypoxia and leads to a self-perpetuating cycle of reciprocal causation, further exacerbating hepatic lipid deposition. Additionally, accumulated HIF-2α plays a critical role in this complex-origin steatosis, potentially through ATF4."

Journal • Metabolic Disorders • ATF4 • EPAS1 • TCF4