MK-3795 / Merck (MSD) - LARVOL DELTA

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

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

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

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

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

In Obesity, Esophagogastric Junction Fat Impairs Esophageal Barrier Function and Dilates Intercellular Spaces via HIF-2α. (PubMed, Gastroenterology) - "We have elucidated molecular mechanisms whereby visceral fat of obese patients can impair esophageal barrier integrity by secreting substances that generate ROS, which activate HIF-2α in esophageal epithelial cells. These mechanisms could render the esophagus of obese individuals vulnerable to damage by acid and other noxious agents."

Journal • Gastroesophageal Reflux Disease • Genetic Disorders • Obesity • EPAS1 • IL1B • IL1R1

RO4929097 inhibits NICD3 to alleviate pulmonary hypertension via blocking Notch3/HIF-2α/FoxM1 signaling pathway. (PubMed, In Vitro Cell Dev Biol Anim) - "RO4929097 and plasmids including overexpression-NICD3 (oe-NICD3) and NICD3 small interfering RNA (siRNA) were used to alter the expression of NICD3, and HIF-2α inhibitor PT-2385 was used to alter the expression of HIF-2α. Our data suggest that RO4929097 regulates the Notch3/HIF-2α/FoxM1 signaling pathway by inhibiting the expression of NICD3, thereby inhibiting hypoxia-induced proliferation of HPASMCs. In vivo experiments also confirmed that RO4929097 could alleviate PH as a potential therapeutic strategy."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • EPAS1 • FOXM1 • NOTCH3

IRON REGULATORY PROTEIN 2 CONTRIBUTES TO ANTIMICROBIAL IMMUNITY BY PRESERVING LYSOSOMAL FUNCTION IN MACROPHAGES (AASLD 2024) - "Tfeb mislocalization was reversed by Hif2 inhibitor PT2385 and, independently, through the inhibition of lactic acid production...Tfeb mislocalization was reversed by Hif2 inhibitor PT2385 and, independently, through the inhibition of lactic acid production. Our study highlights a mechanism whereby IRP2 preserves macrophage lysosomal function in antimicrobial activity to protect the liver against gut-originated bacterial invasion, shedding light on therapeutic intervention for patients with PLA."

Colorectal Cancer • Crohn's disease • Gastroenterology • Gastrointestinal Cancer • Hepatology • Immunology • Infectious Disease • Inflammatory Bowel Disease • Oncology • Solid Tumor • LDHA • TFEB

A pH-responsive novel delivery system utilizing carbon quantum dots loaded with PT2385 for targeted inhibition of HIF-2α in the treatment of osteoarthritis. (PubMed, Int J Pharm) - "The BCP drug delivery system exhibits selective release of PT2385 in response to pH changes occurring during the progression of osteoarthritis (OA), thereby inhibiting HIF-2α expression deep within the cartilage. The use of BCP significantly augments the capacity of PT2385 to retard both cartilage degeneration and the progression of osteoarthritis. Consequently, BCP as an innovative approach utilizing m-CQDs to deliver PT2385 into articular cartilage, shows potential for treating osteoarthritis.This strategy opens new avenues for osteoarthritis treatment."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • EPAS1 • MMP13

Genetic and Epigenetic Regulation of Cortactin (CTTN) by Inflammatory Factors and Mechanical Stress in Human Lung Endothelial Cells. (PubMed, Biosci Rep) - "CTTN transcriptional is significantly influenced by inflammatory factors and promoter variants. Cortactin, essential in mitigating inflammatory edema, presents a promising therapeutic target to alleviate severe inflammatory disorders."

Journal • Inflammation • CTTN • EPAS1 • HIF1A • TNFA

The 'ABC' of split-nanoluciferase HIF heterodimerization bioassays: Applications, benefits & considerations. (PubMed, Biochem Pharmacol) - "This study shows that the application of similar or diverse assay protocols allows to detect various influences on HIF heterodimerization as a key signaling event in the oxygen sensing pathway: increased HIF heterodimerization (roxadustat, MG-132), decreased HIF heterodimerization (PX-478, ibuprofen) and direct (HIF isoform-selective) heterodimerization inhibiting effects (PT-2385). Specific and general considerations include cell-based, technical and disease/drug-related aspects (e.g., non-specific effects, color interference). In summary, the versatility of these bioassays offers benefits in widespread applications regarding drug discovery and pharmacological characterization of various therapeutics, applying either the same or optimized experimental protocols."

Journal • Hematological Disorders • Oncology • HIF1A

Iron regulatory protein 2 contributes to antimicrobial immunity by preserving lysosomal function in macrophages. (PubMed, Proc Natl Acad Sci U S A) - "Tfeb mislocalization was reversed by hypoxia-inducible factor 2 inhibitor PT2385 and, independently, through inhibition of lactic acid production. These experimental findings were confirmed clinically in patients with Crohn's disease and through bioinformatic searches in databases from Crohn's disease or ulcerative colitis biopsies showing loss of IRP2 and transcription factor EB (TFEB)-dependent lysosomal gene expression. Overall, our study highlights a mechanism whereby Irp2 supports nuclear translocation of Tfeb and lysosomal function, preserving macrophage antimicrobial activity and protecting the liver against invading bacteria during intestinal inflammation."

Journal • Colorectal Cancer • Crohn's disease • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Hepatology • Immunology • Infectious Disease • Inflammatory Bowel Disease • Oncology • Solid Tumor • Ulcerative Colitis • LYZ • TFEB

Ameliorating effects of the HIF-2α inhibitor PT2385 on high-altitude polycythemia. (PubMed, Eur J Pharm Sci) - "This study preliminarly explains the physiological, pathological, and immunological effects of PT2385 treatment for HAPC. It provides a new idea, a reliable experimental basis, and theoretical support for the clinical prevention and treatment of HAPC."

Journal • Inflammation • EPAS1

The role of hypoxia inducible factor modulation and defatting in discarded steatotic human livers preserved with normothermic machine perfusion (NMP): observations from an ex-situ whole blood transplant model (TTS 2024) - "We have previously reported dosing schedules for pharmacological HIF modulators including deferoxamine (DFO, a potent activator of both HIF-1a & HIF-2a) with selective HIF-2a inhibition using PT2385 (a HIF-2a dimerisation inhibitor) during NMP. The aim of the present study was to compare the effect of an established NMP defatting protocol (DeFat, comprising of insulin/glucose reduction, L-carnitine, NKH477 and lipid filter) with and without the adjunct of HIF modulators (DeFat-HIF, addition of DFO & PT2385) during ex-situ perfusion. Six sequential discarded livers (DeFat, n=3 and DeFat-HIF, n =3) were perfused with pRBC using the OrganOx metra over 12h, flushed and reperfused for 6h with whole blood (ex-situ transplant model), (Table1)... The DeFat-HIF protocol demonstrated a decrease in the presence of Ld-MaS and comparable perfusion biochemistry to the established DeFat protocol. The effect of these interventions on ischaemia-reperfusion injury remain to be..."

Reperfusion Injury • Transplantation • EPAS1 • HIF1A

PET Imaging of HIF-2a in Renal Cancer (KCRS 2024) - P1 | "PT2977 DoD CDMRP/KCRP Awards (FY2022) differs from PT2385 in that it consists of a vicinal difluoro group instead of a germinal one in PT2385. If successful, the theranostic method developed in this project may become transformative not only in oncology, but also in other diseases such as cardiac ischemia or strokes. FY22 KCRP Focus Area Addressed: Identify and develop new strategies for screening, early-stage detection, and accurate diagnosis and prognosis prediction of kidney cancers, with examples including biomarkers and imaging Principal Investigator: SUN, XIANKAI Institution Receiving Award: UNIVERSITY OF TEXAS SOUTHWESTERN Program: KCRP Proposal Number: KC220060 Award Number: HT9425-23-1-0903 Funding Mechanism: Translational Research Partnership Award Award Amount: $834,798"

IO biomarker • Cardiovascular • Clear Cell Renal Cell Carcinoma • Coronary Artery Disease • Ischemic stroke • Kidney Cancer • Myocardial Ischemia • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1

A Phase 1, Dose-Escalation Trial of PT2385 Tablets In Patients With Advanced Clear Cell Renal Cell Carcinoma (MK-3795-001) (clinicaltrials.gov) - P1 | N=110 | Active, not recruiting | Sponsor: Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Trial completion date: Nov 2024 ➔ Nov 2026

Metastases • Trial completion date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Epithelial HIF Activation Impairs Distal Airway Derived Alveolar Repair (ATS 2024) - "Roxadustat, a prolyl-hydroxylase inhibitor, was used to activate HIF-driven signaling...Administration of HIF2α inhibitor (PT-2385) attenuated emergence of IPF-like cell states, which based on RNA-trajectory analysis were derived from distal-airway progenitors... Persistent HIF activation in the alveolar epithelium prevents maturation and terminal differentiation of regenerating AT2 cells from airway progenitors through suppression of essential AT2 biosynthetic components and metabolic machinery. HIF2 inhibition represents a novel therapeutic target to enhance alveolar repair."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • ACACA • ACSL1 • ACSL4 • FASN • KRT17 • KRT5 • LPCAT1

Candida albicans accelerates atherosclerosis by activating intestinal hypoxia-inducible factor2α signaling. (PubMed, Cell Host Microbe) - "Administration of the HIF-2α selective antagonist PT2385 alleviates atherosclerosis in mice by reducing ceramide levels. Our findings identify a role for intestinal fungi in atherosclerosis progression and highlight the intestinal HIF-2α-ceramide pathway as a target for atherosclerosis treatment."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Metabolic Disorders • EPAS1

Renal Surgery following HIF2α Antagonist Therapy: Growth Kinetics and Surgical Outcomes (AUA 2024) - "Two HIF2α inhibitors, PT2385 and PT2977 (Belzutifan), have shown efficacy and led to the recent FDA approval for Belzutifan in patients with tumors from VHL syndrome. This is the first study to detail the growth kinetics and surgical outcomes of renal tumors removed after HIF2α antagonist exposure. There was no significant difference between the growth rates of the index tumor before, during, or after HIF2α antagonist therapy (p=0. 79)."

Surgery • Cardiovascular • Kidney Cancer • Oncology • Renal Cell Carcinoma • Respiratory Diseases • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1 • VHL

Chronic hypoxia impairs skeletal muscle repair via HIF-2α stabilization. (PubMed, J Cachexia Sarcopenia Muscle) - "Chronic hypoxia detrimentally affects skeletal muscle regeneration by stabilizing HIF-2α in MuSC and thereby diminishing MuSC proliferation. HIF-2α increases local ACE levels in skeletal muscle, contributing to hypoxia-induced regenerative deficits. Administration of HIF-2α or ACE inhibitors may prove beneficial to ameliorate chronic hypoxia-associated muscle atrophy and weakness by improving muscle regeneration under chronic hypoxia."

Journal • Chronic Obstructive Pulmonary Disease • Fibrosis • Immunology • Muscular Atrophy • Pulmonary Disease • Respiratory Diseases • EPAS1 • HIF1A