PT2399 / Merck (MSD) - LARVOL DELTA

EPAS1 knockdown is associated with cell cycle and DNA replication programs and MYC/E2F-related signatures in hemangioma endothelial cells. (PubMed, PLoS One) - "Here, we investigated HIF-2α in primary HemECs using a pharmacological inhibitor (PT-2399) and shRNA-mediated EPAS1 knockdown under normoxic and hypoxic conditions...In IH tissue transcriptomic data, Egl-9 family hypoxia-inducible factor 3 (EGLN3) showed reduced expression, consistent with a testable hypothesis that hypoxia-independent mechanisms may contribute to maintenance of HIF-2α activity in this context. This study is limited by the use of HemECs derived from a single IH specimen and by the absence of on-target validation; accordingly, the findings should be interpreted as exploratory and hypothesis-generating."

Journal • Oncology • EGLN3 • EPAS1

Tumor neutrophils mediate immunosuppression through the hypoxia-EGR1-PTGS2 signaling axis in advanced head and neck carcinomas unrelated to HPV (AHNS 2026) - "Here, using DMSO-differentiated HL60 cells as a model for human neutrophils, we show that hypoxia-induced EGR1 expression is reduced in the presence of the IRE-1/ER stress inhibitor B-I09 or the MEK1/2 inhibitor trametinib but not reduced in the presence of the HIF1 inhibitor BAY87-2243 or the HIF2 inhibitor PT2399...Importantly, immunosuppressive function of human peripheral blood neutrophils exposed to hypoxia was abrogated in the presence of celecoxib (COX2 inhibitor) but not OSM or IL-1b neutralization, confirming the role of PGE2 in hypoxic neutrophil immunosuppression...Together, these data indicate that tumor neutrophils immunosuppress T cell function through the function of COX2 and downstream production of PGE2 and that this pathway can be abrogated with MAPK-pathway inhibition, possibly resulting in enhanced response to immunotherapy. This data informs neoadjuvant combination immunotherapy studies in patients with advanced head and neck carcinomas that aim to..."

IO biomarker • Metastases • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • EGR1 • ERN1 • HIF1A • IL1B • PACERR • PTGS2

An optimized "hypoxia in a pill" regimen reverses neurodegenerative disease phenotypes in multiple preclinical models. (PubMed, bioRxiv) - "We previously introduced a small molecule, "hypoxia-in-a-pill" regimen that combines the hemoglobin affinity enhancer (GBT440) -- which limits oxygen delivery to tissues -- with a HIF-2α inhibitor (PT2399) to prevent compensatory erythropoiesis that can be detrimental. Importantly, body weight was stable with the combination and it did not induce any signs of pulmonary hypertension, likely due to attenuation of HIF-2α. Our findings motivate additional pre-clinical and even clinical studies to evaluate the safety and efficacy of the GBT601/PT2399 combination."

Journal • Preclinical • Ataxia • Cardiovascular • CNS Disorders • Friedreich ataxia • Hypertension • Metabolic Disorders • Movement Disorders • Parkinson's Disease • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • EPAS1

Deciphering the mechanistic basis of HIFxcexb1 paralog target selectivity in kidney cancer* (AACR-Kidney 2026) - "Chimeras containing HIF1α-NT fused to HIF2α-TAD restored HIF2α target gene expression and proliferation in PT2399-treated cells, whereas the reciprocal chimera failed to do so, even with a PT2399-resistance mutation in HIF2α-NT. Belzutifan, an inhibitor that blocks HIF2α-ARNT dimerization, is FDA-approved for ccRCC treatment, but resistance mutations preventing drug binding or HIF2α-ARNT disruption have been reported. In conclusion, the findings from this study reveal an unexpected mechanism in which post-transcriptional RNA-abundance regulators contribute to HIF2α-specific transcription, highlighting new therapeutic avenues for small-molecule HIF2α inhibition and for overcoming resistance to current HIF2α-targeted therapies."

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • DCK • HIF1A • TNRC6A

Profiling the ccRCC surfaceome reveals SEMA5B as a potential therapeutic membrane target (AACR-Kidney 2026) - "Using 786-O and OSRC2 ccRCC VHL-/- cell lines engineered to re-express VHL in a DOX-inducible manner, we profiled surfaceome changes upon DOX, HIF2a inhibitor PT2399 or DMSO treatment...Additionally, Orthotopic xenograft assays demonstrated that SEMA5B loss impaired tumor growth, which was rescued by exogenous re-expression, indicating its essential role in ccRCC tumorigenic activity in vivo. Our study establishes oncogene-driven surfaceome profiling as a robust strategy to uncover cancer-specific vulnerabilities and highlights SEMA5B as a potential therapeutic membrane target in ccRCC, paving the way for the development of precision-targeted therapies and immunotherapies that exploit the unique surface landscape of cancer cells."

IO biomarker • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1 • NDRG1 • SLC2A1

Inhibition of the HIF-2α-PTHrP axis ameliorates paraneoplastic hypercalcemia in clear cell renal cell carcinoma (AACR-Kidney 2026) - "The effects of pharmacologic HIF-2α inhibition were tested in TGs using PT2399 and in patients using PT2977.ResultsIn TG(HC), PTHLH locus remained uniquely accessible. Therapeutic inhibition of HIF-2 rapidly alleviates HC by suppressing PTHrP production, supporting a mechanism-driven treatment strategy. Further the study highlights HC/ PTHrP as a potential predictive biomarker of HIF-2 pathway dependence, forming the base for clinical evaluation."

Clear Cell Renal Cell Carcinoma • Endocrine Disorders • Genito-urinary Cancer • Metabolic Disorders • Oncology • Renal Cell Carcinoma • Rhabdoid Tumor • Sarcoma • Solid Tumor • EPAS1 • PTHLH

HIF2-dependent regulation of paraneoplastic hypercalcemia in aggressive clear cell renal cell carcinoma (ESMO 2025) - "Methods To study the role of HIF2 in HHM, we deployed a specific inhibitor, PT2399 (an analogue of PT2977/belzutifan), and retrieved from our RCC PDX collection (n>150) PDXs that, as in patients, induced HHM in host mice. Conclusions These data support the clinical evaluation of HIF2 antagonists for HHM in ccRCC and suggest that HHM and more broadly, PTHrP reduction (even within the normal range), may serve as predictive biomarkers of response. Legal entity responsible for the study The authors."

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Rhabdoid Tumor • Sarcoma • Solid Tumor • EPAS1 • PTHLH

HIF-2-dependent Regulation of PTHrP and Paraneoplastic Hypercalcemia in Aggressive Clear Cell Renal Cell Carcinoma. (PubMed, Cancer Discov) - "Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. As in TGs, paraneoplastic HC in patients was associated with clear cell (cc)RCC (and sarcomatoid/rhabdoid differentiation) and was rapidly corrected by PT2977/belzutifan, which unlike bisphosphonates, downregulated PTHrP. Our data supports evaluating HIF-2 antagonists for ccRCC patients with paraneoplastic HC, which may serve as a predictive biomarker."

Journal • Clear Cell Renal Cell Carcinoma • Endocrine Disorders • Genito-urinary Cancer • Metabolic Disorders • Oncology • Renal Cell Carcinoma • Rhabdoid Tumor • Sarcoma • Solid Tumor

Determining the impact of HIF2a inhibition on T cell function in clear cell renal cell carcinoma (KCRS 2025) - "Belzutifan, a HIF2 a inhibitor, was recently approved as a treatment for refractory, sporadic advanced RCC, and is under investigation in combination with pembrolizumab in the adjuvant (LITESPARK-022) and first-line metastatic (LITESPARK-012) setting...For functional assays, T cells were treated with DMSO (vehicle), tacrolimus (control for effective inhibition of T cell function), or HIF2 a inhibitors (belzutifan or PT2399)...In the settings examined, HIF2 a inhibition did not impair T cell function, suggesting that combination with immune checkpoint inhibitors remains a viable therapeutic strategy pending results of ongoing clinical studies. Ongoing laboratory-based assessment will assess the impact of prolonged HIF2 a inhibition on T cell phenotype, evaluate its effects on direct cytotoxicity using antigen-specific RCC killing assays, and examine potential synergy with anti–PD-1 therapy."

IO biomarker • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CD4 • CD8 • EPAS1 • IFNG • IL2 • TNFA

BMAL1 and ARNT enable circadian HIF2α responses in clear cell renal cell carcinoma. (PubMed, Nat Commun) - "BMAL1-HIF2α is more sensitive than ARNT-HIF2α is to suppression by PT2399, and the effectiveness of PT2399 for suppressing xenograft tumor growth in vivo depends on the time of day at which it is delivered. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 influences HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • ARNTL • BMAL1 • EPAS1

Pharmacological inhibition of HIF2 protects against bone loss in an experimental model of estrogen deficiency. (PubMed, Proc Natl Acad Sci U S A) - "More importantly, PT2399, a small molecule that specifically inhibits HIF2, effectively prevents trabecular bone loss in ovariectomized adult mice, a model for estrogen-deficient bone loss. Both the genetic and pharmacological approaches result in an increase in osteoblast number, which is linked to the expansion of the pool of skeletal progenitor cells. This expansion either by loss or inhibition of HIF2 uncovers a pivotal mechanism for increasing osteoblast numbers and bone formation, resulting in greater trabecular bone mass."

Journal • Endocrine Disorders • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology • Women's Health

Toward a CRISPR-based mouse model of Vhl-deficient clear cell kidney cancer: Initial experience and lessons learned. (PubMed, Proc Natl Acad Sci U S A) - "An AAV targeting Vhl, Pbrm1, Keap1, and Tsc1 reproducibly caused macroscopic ccRCCs that partially resembled human ccRCC tumors with respect to transcriptome and cell of origin and responded to a ccRCC standard-of-care agent, axitinib. Unfortunately, these tumors, like those produced by earlier genetically engineered mouse ccRCCs, are HIF2 independent."

Journal • Preclinical • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • KEAP1 • PAX8 • PBRM1 • VHL

BMAL1-HIF2α heterodimers contribute to ccRCC. (PubMed, Res Sq) - "We show that BMAL1-HIF2α is more sensitive than ARNT-HIF2α to suppression by PT2399, and increasing BMAL1 sensitizes 786O cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • Von Hippel-Lindau Syndrome • ARNTL • BMAL1 • CLOCK • EPAS1

BMAL1-HIF2α heterodimers contribute to ccRCC. (PubMed, bioRxiv) - "We show that BMAL1-HIF2α is more sensitive than ARNT-HIF2α to suppression by PT2399, and increasing BMAL1 sensitizes 786O cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • ARNTL • BMAL1 • CLOCK • EPAS1

HIF-2α Inhibition Disrupts Leukemia Stem Cell Metabolism and Impairs Vascular Microenvironment to Enhance Chronic Myeloid Leukemia Treatment. (PubMed, Cancer Lett) - "Furthermore, pharmaceutical inhibition of HIF-2α by PT2399 attenuates disease progression and improves the efficacy of TKI treatment in both mouse and human CML. Overall, our findings highlight the role of HIF-2α in controlling the metabolic state and vascular niche remodeling in CML, suggesting it is a potential therapeutic target to enhance TKI therapy."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • EPAS1

Unveiling the role of hypoxia-inducible factor 2alpha in osteoporosis: Implications for bone health. (PubMed, World J Stem Cells) - "Our study showed that inhibition of HIF-2α decreases bone mass by inhibiting the osteogenic differentiation and increasing the adipogenic differentiation of BMSCs through inhibition of mTOR signaling in the BM niche."

Journal • Osteoporosis • Rheumatology • EPAS1

Poly-3-hydroxybutyrate-co-3-hydroxyvalerate(PHBV)-Polyethylene glycol 20k(PEG20k) as a promising delivery system for PT2399 in the treatment of disc degeneration. (PubMed, J Biol Eng) - "Additionally, HIF-2α might contribute to the progression of disc degeneration through involvement in angiogenesis and the regulation of hypoxia. Furthermore, the utilization of PT2399 loaded PHBV-PEG20k (PP20) could potentially offer a fresh alternative for treating disc degeneration."

Journal • Back Pain • Lumbar Back Pain • Musculoskeletal Pain • Pain • CA9 • EGLN3 • EPAS1 • PPP1R15A

Radiation-induced bone loss in mice is ameliorated by inhibition of HIF-2α in skeletal progenitor cells. (PubMed, Sci Transl Med) - "Nanocarrier-loaded PT2399 prevented radiation-induced bone loss in mice while reducing drug accumulation in the kidney. Targeted inhibition of HIF-2α may represent a therapeutic approach for protecting bone during radiation therapy."

Journal • Preclinical • Hematological Disorders • Oncology • Osteoporosis • EPAS1 • LEP • LEPR

Cancer-associated fibroblasts modulate macrophage phenotype in PDAC through hypoxia inducible factor-2(HIF2)-dependent IGFBP3 secretion (AACR 2023) - "HIF2 was also inhibited with the small molecule PT2399... Our results suggest that HIF2-dependent secretion of IGFBP3 from CAFs in the hypoxic pancreatic cancer TME contributes to its immunosuppressive nature. Future work will focus on verifying that IGFBP3 mediates HIF2-dependent modulation of macrophages and will explore other paracrine factors which may be involved in CAF-macrophage crosstalk."

Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs • IGFBP1 • IGFBP3 • IGFBP7 • MRC1

Targeting HIF2a with siRNA: From preclinical models to the clinic (AACR 2022) - P1b | "Referring herein to both first- and second-generation (ARO-HIF2) siRNA drugs, siHIF2 is specifically taken up by human ccRCC tumors transplanted in mice, where it depletes HIF2a inhibiting target gene expression and tumor growth...siHIF2 has activity against both wild-type and drug-resistant mutant HIF2a and is expected to be active in patients progressing on PT2977 (belzutifan), a PT2399-related drug recently approved by the FDA. To our knowledge, this is the first example of functional inactivation of an oncoprotein with a tumor-directed siRNA in humans. In summary, these studies provide unique insight into HIF2a (the only known core dependency in ccRCC), illustrate how it can be effectively inhibited by an siRNA drug, and establish a paradigm for the development of tumor directed siRNA-based therapeutics."

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

Development of a novel HIF2a PET tracer: From proof of concept to a clinical trial (AACR 2022) - P1 | "While as a transcription factor HIF2a had escaped drug targeting, structural studies revealed an unusual cavity, which became the foundation for the development of small molecule inhibitors such as PT2385 (a first-in-class drug), or the related PT2399 tool compound and the recently FDA-approved PT2977 (also called belzutifan). Reporting on a hypoxia sensor, a HIF2a radiotracer may be a useful ischemia probe. In summary, we report the development of a novel radiotracer with extensive potential applications currently being evaluated in humans."

Clinical • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • ARNT • EPAS1 • HIF1A • VHL

Targeting HIF-2α for the Treatment of CML By Affecting LSCs Metabolism and the Vascular Microenvironment (ASH 2022) - "In conclusion, HIF-2α knockout could inhibit the function of LSCs by affecting their metabolic pattern and vascular microenvironment in CML. Therefore, targeting HIF-2α may become a new strategy, and its specific inhibitor PT2399 may be a candidate drug for clinical application in CML treatment."

IO biomarker • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Transplantation • ABL1 • BCR • CD34 • EPAS1 • HIF1A • THY1

Targeting HIF2a inhibitor resistance in clear cell renal cell carcinoma (KCRS 2022) - "Methods We have treated ccRCC cell line 786-O with PT2399, a structure analog of MK-6482, for an extended period of time. Conclusions In conclusion, we have estabilished the experimental system to examine molecular mechanism on the adaptive resistance to HIF-2a inhibitor and to explore the potential pathways as drug targets, which may provide alternative treatment strategies for HIF-2a inhibitor-resistant patients. Keywords: HIF2a, therapeutic resistance, ccRCC"

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

HIF2 inactivation and tumor suppression with a tumor-directed RNA-silencing drug in mice and humans. (PubMed, Clin Cancer Res) - P1b | "To our knowledge, this is the first example of functional inactivation of an oncoprotein and tumor suppression with a systemic, tumor-directed, RNA-silencing drug. These studies provide a proof-of-principle of HIF2α inhibition by RNA-targeting drugs in ccRCC and establish a paradigm for tumor-directed RNA-based therapeutics in cancer."

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

Loss of VHL Activates SFMBT1- SPHK1 Oncogenic Signaling in Kidney Cancer (KCRS 2022) - "Recent reports showed that the specific HIF2alpha inhibitor PT2399 inhibits primary tumor growth and invasion of a subset of kidney cancer...Also, if successful, our work will provide new therapeutic avenues in kidney cancer by targeting the SFMBT1-SPHK1 oncogenic signaling axis. Personally, this research project will provide a strong foundation for me to develop a career at the forefront of kidney cancer research."

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Targeted Protein Degradation • Von Hippel-Lindau Syndrome • EPAS1 • HIF1A • VHL