PT2399 / Merck (MSD) - LARVOL DELTA

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

SGLT2 inhibitor dapagliflozin attenuates cardiac fibrosis and inflammation by reverting the HIF-2α signaling pathway in arrhythmogenic cardiomyopathy. (PubMed, FASEB J) - "Excessive cardiac fibrosis and inflammation aberrantly contribute to the progressive pathogenesis of arrhythmogenic cardiomyopathy (ACM). Interestingly, the elective HIF-2α inhibitor PT2399 almost completely blunted the DAPA-mediated downregulation of indicators concerning cardiac fibrosis and inflammation. SGLT2i attenuated the ACM-associated cardiac dysfunction and adverse remodeling in a glucose-independent manner by suppressing cardiac fibrosis and inflammation via reverting the HIF-2α signaling pathway, suggesting that SGLT2i is a novel and available therapy for ACM."

Journal • Cardiomyopathy • Cardiovascular • Fibrosis • Immunology • Inflammation • EPAS1 • HIF1A • TGFB1

Hypoxia-reoxygenation couples 3βHSD1 enzyme and cofactor upregulation to facilitate androgen biosynthesis and hormone therapy resistance in prostate cancer. (PubMed, Cancer Res) - "Inhibition of HIF2α with the small molecule PT2399 prevented prostate cancer cell proliferation. These results thus identify HIF2α as a regulator of androgen synthesis and potential therapeutic target in prostate cancer."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • EGLN1 • EPAS1 • HSD3B1

Hypoxia-reoxygenation couples enzyme and cofactor upregulation to quicken prostate cancer androgen biosynthesis and hormone therapy resistance (AACR 2022) - "PT2399, a specific HIF2α inhibitor, prevented prostate cancer cell proliferation. Our study indicates HIF2α is a potential therapeutic target in prostate cancer."

Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • EGLN1 • HSD3B1

Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment. (PubMed, Gastroenterology) - "Together, these data suggest that stromal HIF2 is an essential component of PDAC pathobiology and is a druggable therapeutic target that could relieve tumor microenvironment immunosuppression and enhance immune responses in this disease."

IO biomarker • Journal • Fibrosis • Gastrointestinal Cancer • Hepatology • Immune Modulation • Immunology • Inflammation • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CAFs • EPAS1 • HIF1A

Therapeutic Effects of Inhibition of Sphingosine-1-Phosphate Signaling in HIF-2α Inhibitor-Resistant Clear Cell Renal Cell Carcinoma. (PubMed, Cancers (Basel)) - "Here we investigated the effects on tumor growth and on the tumor microenvironment of three different direct and indirect HIF-α inhibitors, namely the HIF-2α-specific inhibitor PT2399, the dual HIF-1α/HIF-2α inhibitor Acriflavine, and the S1P signaling pathway inhibitor FTY720, in the autochthonous Vhl/Trp53/Rb1 mutant ccRCC mouse model and validated these findings in human ccRCC cell culture models. We also identify that HIF-2α inhibition strongly suppresses T cell activation in ccRCC. These findings suggest prioritization of sphingosine pathway inhibitors for clinical testing in ccRCC patients and also suggest that HIF-2α inhibitors may inhibit anti-tumor immunity and might therefore be contraindicated for combination therapies with immune checkpoint inhibitors."

IO biomarker • Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Immune Modulation • Inflammation • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • HIF1A • RB1

Hypoxia and its possible relationship with endometrial receptivity in adenomyosis: a preliminary study. (PubMed, Reprod Biol Endocrinol) - "HIF-2α overexpression may be one reason for decreased endometrial receptivity in AM. The current findings provide insight into HIF-2α-mediated AM-related infertility and suggest that PT2399 has potential as a treatment for AM."

Journal • Endometriosis • Gynecology • Infertility • Sexual Disorders