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    DRUG CLASS:

    HIF-2α inhibitor

    Related drugs:
    6d
    LITESPARK-015: Belzutifan/MK-6482 for the Treatment of Advanced Pheochromocytoma/Paraganglioma (PPGL), Pancreatic Neuroendocrine Tumor (pNET), Von Hippel-Lindau (VHL) Disease-Associated Tumors, Advanced Gastrointestinal Stromal Tumor (wt GIST), or Solid Tumors With HIF-2α Related Genetic Alterations (MK-6482-015) (clinicaltrials.gov)
    P2, N=322, Recruiting, Merck Sharp & Dohme LLC | N=171 --> 322
    Enrollment change
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    Welireg (belzutifan)
    6d
    Glucocorticoids elevate clear cell renal cell carcinoma sensitivity to HIF-2α inhibitors by suppressing H4K12 lactylation. (PubMed, Signal Transduct Target Ther)
    Strikingly, VHL-deficient ccRCC exhibits greater on-target pathway sensitivity to dexamethasone at the H4K12la-glycolysis axis, and glucocorticoid dexamethasone potentiated the antitumor efficacy of the HIF-2α inhibitor belzutifan in both orthotopic cell line-derived and patient-derived xenograft models. Collectively, our findings establish H4K12la as a metabolic‒epigenetic amplifier in VHL-deficient ccRCC, reposition glucocorticoids as epigenetically active modulators that dampen lactate-driven chromatin activation and glycolytic output, and provide a mechanistically grounded combination strategy with HIF-2α blockade to target lactate-fueled transcriptional dependence in metabolically rigid tumors.
    Journal
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    EPAS1 (Endothelial PAS domain protein 1) • PGK1 (Phosphoglycerate Kinase 1)
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    dexamethasone • Welireg (belzutifan)
    7d
    Very rapid response to belzutifan of VHL-related intracranial and retinal hemangioblastomas. (PubMed, Am J Ophthalmol Case Rep)
    A slight but measurable improvement in visual acuity was also observed, despite the overall structural stability of the RH. These findings support the potential value of early radiological and functional assessment in selected patients receiving HIF-2α inhibitors.
    Journal
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    EPAS1 (Endothelial PAS domain protein 1)
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    Welireg (belzutifan)
    14d
    Genome-wide CRISPR screen identifies a cytokine-enhancer circuit driving HIF-2α activation in renal cancer. (PubMed, J Clin Invest)
    Resistance to HIF-2α inhibitors such as Belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC)...Unlike prior studies focusing on VHL/HIF occupancy-driven enhancer activation, this work defines a trans-acting cytokine-JAK1-STAT3 pathway that transcriptionally controls EPAS1. Together, these findings reveal a targetable enhancer mechanism that sustains HIF-2α expression and suggest that combined inhibition of JAK1/STAT3 and HIF-2α may overcome therapeutic resistance in kidney cancer.
    Journal
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    JAK1 (Janus Kinase 1) • EPAS1 (Endothelial PAS domain protein 1) • SOCS3 (Suppressor Of Cytokine Signaling 3)
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    Welireg (belzutifan)
    15d
    A Clinical Study of Belzutifan (MK-6482) and Zanzalintinib in People With Renal Cell Carcinoma (RCC) (LITESPARK-034/LS-034/MK-6482-034) (clinicaltrials.gov)
    P3, N=758, Not yet recruiting, Merck Sharp & Dohme LLC
    New P3 trial
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    Welireg (belzutifan) • zanzalintinib (XL092)
    18d
    Pre-NEOSHIFT-RCC: Neoadjuvant HIF-Inhibitor Immunotherapy in RCC (clinicaltrials.gov)
    P2, N=32, Recruiting, Dana-Farber Cancer Institute | Not yet recruiting --> Recruiting | Initiation date: Jul 2026 --> Mar 2026
    Enrollment open • Trial initiation date
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    Yutuo (zimberelimab) • casdatifan (AB521)
    20d
    Extension Study for Participants in Studies That Include Belzutifan (MK-6482-043/LITESPARK-043) (clinicaltrials.gov)
    P3, N=450, Recruiting, Merck Sharp & Dohme LLC | Not yet recruiting --> Recruiting
    Enrollment open
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    Opdivo (nivolumab) • Ibrance (palbociclib) • everolimus • Lenvima (lenvatinib) • Cabometyx (cabozantinib tablet) • Welireg (belzutifan)
    23d
    LITESPARK-033: A Clinical Study of Belzutifan and Zanzalintinib in People With Recurrent Kidney Cancer Following Adjuvant Therapy (MK-6482-033) (clinicaltrials.gov)
    P3, N=904, Recruiting, Merck Sharp & Dohme LLC
    Trial initiation date
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    Cabometyx (cabozantinib tablet) • Welireg (belzutifan) • zanzalintinib (XL092)
    25d
    Oncometabolites and Hypoxia-Regulated Exosomes Shape HIF-Driven Macrophage Programs Across Type 2 Diabetes, Atherosclerosis, and Cancer. (PubMed, Int J Mol Sci)
    Translational entry points include selective HIF-2α inhibition, phosphoinositide 3-kinase gamma (PI3Kγ) blockade, SUCNR1 targeting, and exosome-based miRNA modulation, while a biomarker panel comprising HIF-1α, vascular endothelial growth factor A (VEGF-A), and MMP-9 offers a pragmatic readout of hypoxia burden, macrophage programming, and therapeutic response. We conducted a focused narrative review (PubMed, Scopus, Web of Science; English; 2003-2025), prioritizing mechanistic and translational studies on hypoxia-HIF, lactate/succinate, and hypoxia-regulated exosomes across T2D, atherosclerosis, and cancer.
    Review • Journal • PD(L)-1 Biomarker • IO biomarker
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    PD-L1 (Programmed death ligand 1) • PTEN (Phosphatase and tensin homolog) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma) • EPAS1 (Endothelial PAS domain protein 1) • MMP2 (Matrix metallopeptidase 2) • MMP9 (Matrix metallopeptidase 9) • CCR2 (C-C Motif Chemokine Receptor 2) • ABCA1 (ATP Binding Cassette Subfamily A Member 1) • SUCNR1 (Succinate Receptor 1)
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    PD-L1 expression
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    Welireg (belzutifan)
    30d
    LITESPARK-033: A Clinical Study of Belzutifan and Zanzalintinib in People With Recurrent Kidney Cancer Following Adjuvant Therapy (MK-6482-033) (clinicaltrials.gov)
    P3, N=904, Recruiting, Merck Sharp & Dohme LLC
    Trial initiation date
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    Cabometyx (cabozantinib tablet) • Welireg (belzutifan) • zanzalintinib (XL092)
    1m
    CDFF332A12101: DFF332 as a Single Agent and in Combination With Everolimus & Immuno-Oncology Agents in Advanced/Relapsed Renal Cancer & Other Malignancies (clinicaltrials.gov)
    P1, N=40, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Business decision and not related to safety concerns
    Trial termination • IO biomarker • First-in-human
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    VHL (von Hippel-Lindau tumor suppressor) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • EPAS1 (Endothelial PAS domain protein 1) • SDHC (Succinate Dehydrogenase Complex Subunit C) • SDHD (Succinate Dehydrogenase Complex Subunit D) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A) • SDHAF2 (Succinate Dehydrogenase Complex Assembly Factor 2)
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    VHL mutation
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    everolimus • spartalizumab (PDR001) • DFF332 • taminadenant (NIR178)
    1m
    ARC-20: A Phase 1 Study of AB521 Monotherapy and Combination Therapies in Renal Cell Carcinoma and Other Solid Tumors (clinicaltrials.gov)
    P1, N=362, Recruiting, Arcus Biosciences, Inc. | Trial completion date: Jul 2027 --> Mar 2029 | Trial primary completion date: Jul 2027 --> Mar 2029
    Trial completion date • Trial primary completion date
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    Yervoy (ipilimumab) • Cabometyx (cabozantinib tablet) • Yutuo (zimberelimab) • casdatifan (AB521)