Belzutifan
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Also known as Mk-6482MK6482Pt 2977PT-2977Pt2977Welireg
Summary
Belzutifan (CHEMBL4585668) is an approved small molecule (ATC L01XX74) targeting EPAS1; indicated across 9 conditions including clear cell renal carcinoma and renal cell carcinoma; with CIViC clinical evidence for 1 variant-indication association (e.g. EPAS1 Overexpression in von hippel-lindau disease).
At a glance
- Status: Approved (max clinical phase 4)
- Modality: Small molecule
- ATC class: L01XX74
- Targets: 1 (EPAS1)
- Indications: 9 conditions
- Clinical trials: 36
- Precision-oncology evidence (CIViC): 1 variant–indication association
- Chemistry: 383.3 Da · C17H12F3NO4S
Identifiers
Drug identity and classification
| Field | Value |
|---|---|
| ChEMBL ID | CHEMBL4585668 |
| Name | Belzutifan |
| Type | Small molecule |
| Max phase | 4 |
| FDA approved | yes |
| PubChem CID | 117947097 |
| ATC | L01XX74 |
| Molecular formula | C17H12F3NO4S |
| Molecular weight | 383.3 |
| InChIKey | LOMMPXLFBTZENJ-ZACQAIPSSA-N |
SMILES: CS(=O)(=O)C1=C2[C@@H]([C@@H]([C@@H](C2=C(C=C1)OC3=CC(=CC(=C3)C#N)F)F)F)O
IUPAC name: 3-[[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-inden-4-yl]oxy]-5-fluorobenzonitrile
Also known as: Belzutifan, Mk-6482, MK-6482, MK6482, Pt 2977, PT-2977, Pt2977, PT2977, Welireg, BELZUTIFAN
Patent coverage: 484 distinct patent families (1,088 SureChEMBL compound mentions), from 4 matched compound structure(s). One matched structure accounts for 973 (89%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.
Targets
Targets
Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).
| Gene | Target | Action | pAffinity | Cancer dependency | UniProt |
|---|---|---|---|---|---|
| EPAS1 | endothelial PAS domain protein 1 | Binding | 8.05 | 0.8% | Q99814 |
Broader ChEMBL bioactivity targets: 2 (assay-derived). Sample: Endothelial PAS domain-containing protein 1, Vascular endothelial growth factor A, long form.
Bioactivity
ChEMBL activities: 8 potent at pChembl ≥ 5 of 8 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):
| Target | pChembl | Type | Value | Unit | Activity ID |
|---|---|---|---|---|---|
| EPAS1 | 8.05 | IC50 | 9 | nM | CHEMBL_ACT_18883394 |
| EPAS1 | 8.05 | IC50 | 9 | nM | CHEMBL_ACT_29055483 |
| EPAS1 | 8 | IC50 | 10 | nM | CHEMBL_ACT_27929765 |
| EPAS1 | 7.96 | EC50 | 11 | nM | CHEMBL_ACT_18883403 |
| EPAS1 | 7.77 | EC50 | 17 | nM | CHEMBL_ACT_18883438 |
| VEGFA | 7.75 | EC50 | 18 | nM | CHEMBL_ACT_27495149 |
| VEGFA | 7.75 | EC50 | 18 | nM | CHEMBL_ACT_27521564 |
| VEGFA | 7.75 | EC50 | 18 | nM | CHEMBL_ACT_27930104 |
Target pathways
Aggregated over 1 target gene(s): EPAS1.
Top Reactome pathways
8 total, by targets touching each:
| Pathway | Targets | Genes |
|---|---|---|
| Regulation of gene expression by Hypoxia-inducible Factor | 1 | EPAS1 |
| Cellular response to hypoxia | 1 | EPAS1 |
| Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha | 1 | EPAS1 |
| Transcriptional regulation of pluripotent stem cells | 1 | EPAS1 |
| PTK6 Expression | 1 | EPAS1 |
| Neddylation | 1 | EPAS1 |
| Pexophagy | 1 | EPAS1 |
| Regulation of PD-L1(CD274) transcription | 1 | EPAS1 |
Dominant GO biological processes
| GO term | Targets |
|---|---|
| angiogenesis | 1 |
| response to hypoxia | 1 |
| embryonic placenta development | 1 |
| blood vessel remodeling | 1 |
| regulation of heart rate | 1 |
| epithelial cell maturation | 1 |
| regulation of transcription by RNA polymerase II | 1 |
| response to oxidative stress | 1 |
| mitochondrion organization | 1 |
| signal transduction | 1 |
| visual perception | 1 |
| erythrocyte differentiation | 1 |
| lung development | 1 |
| intracellular oxygen homeostasis | 1 |
| norepinephrine metabolic process | 1 |
Indications & clinical
Indications
9 indications (7 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).
| Indication | Trial phase | MONDO | EFO |
|---|---|---|---|
| clear cell renal carcinoma | 4 | MONDO:0005005 | EFO:0000349 |
| renal cell carcinoma | 4 | MONDO:0005086 | EFO:0000681 |
| pancreatic neuroendocrine tumor | 4 | MONDO:0019954 | EFO:1000045 |
| hemangioblastoma | 4 | MONDO:0016748 | MONDO:0016748 |
| neoplasm | 4 | MONDO:0005070 | EFO:0000616 |
| von Hippel-Lindau disease | 4 | MONDO:0008667 | MONDO:0008667 |
| renal cell adenocarcinoma | 4 | MONDO:0005549 | EFO:0005708 |
| liver disorder | 1 | MONDO:0005154 | EFO:0001421 |
| chronic kidney disease | 1 | MONDO:0005300 | EFO:0003884 |
Clinical trials
Total trials: 36.
Phase distribution
| Phase | Trials |
|---|---|
| PHASE2 | 11 |
| PHASE1 | 11 |
| PHASE3 | 8 |
| PHASE1/PHASE2 | 5 |
| Not specified | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT04195750 | PHASE3 | ACTIVE_NOT_RECRUITING | A Study of Belzutifan (MK-6482) Versus Everolimus in Participants With Advanced Renal Cell Carcinoma (MK-6482-005) |
| NCT04586231 | PHASE3 | ACTIVE_NOT_RECRUITING | A Study of Belzutifan (MK-6482) in Combination With Lenvatinib Versus Cabozantinib for Treatment of Renal Cell Carcinoma (MK-6482-011) |
| NCT04736706 | PHASE3 | ACTIVE_NOT_RECRUITING | A Study of Pembrolizumab (MK-3475) in Combination With Belzutifan (MK-6482) and Lenvatinib (MK-7902), or Pembrolizumab/Quavonlimab (MK-1308A) in Combination With Lenvatinib, Versus Pembrolizumab and Lenvatinib, for Treatment of Advanced Clear Cell Renal Cell Carcinoma (MK-6482-012) |
| NCT05239728 | PHASE3 | ACTIVE_NOT_RECRUITING | A Study of Belzutifan (MK-6482) Plus Pembrolizumab (MK-3475) Versus Placebo Plus Pembrolizumab in Participants With Clear Cell Renal Cell Carcinoma Post Nephrectomy (MK-6482-022) |
| NCT05899049 | PHASE3 | ACTIVE_NOT_RECRUITING | A Study of Pembrolizumab (MK-3475) in Combination With Belzutifan (MK-6482) and Lenvatinib (MK-7902), or Pembrolizumab/Quavonlimab (MK-1308A) in Combination With Lenvatinib, vs Pembrolizumab and Lenvatinib, for Treatment of Advanced Clear Cell Renal Cell Carcinoma (MK-6482-012)-China Extension Study |
| NCT07227402 | PHASE3 | RECRUITING | A Clinical Study of Belzutifan and Zanzalintinib in People With Recurrent Kidney Cancer Following Adjuvant Therapy (MK-6482-033) |
| NCT07405164 | PHASE3 | RECRUITING | Extension Study for Participants in Studies That Include Belzutifan (MK-6482-043/LITESPARK-043) |
| NCT07489495 | PHASE3 | RECRUITING | A Clinical Study of Belzutifan (MK-6482) and Zanzalintinib in People With Renal Cell Carcinoma (RCC) (LITESPARK-034/LS-034/MK-6482-034) |
| NCT02861573 | PHASE1/PHASE2 | RECRUITING | Study of Pembrolizumab (MK-3475) Combination Therapies in Metastatic Castration-Resistant Prostate Cancer (MK-3475-365/KEYNOTE-365) |
| NCT03401788 | PHASE2 | ACTIVE_NOT_RECRUITING | A Phase 2 Study of Belzutifan (PT2977, MK-6482) for the Treatment of Von Hippel Lindau (VHL) Disease-Associated Renal Cell Carcinoma (RCC) (MK-6482-004) |
| NCT03634540 | PHASE2 | ACTIVE_NOT_RECRUITING | A Trial of Belzutifan (PT2977, MK-6482) in Combination With Cabozantinib in Patients With Clear Cell Renal Cell Carcinoma (ccRCC) (MK-6482-003) |
| NCT04489771 | PHASE2 | ACTIVE_NOT_RECRUITING | A Study of Belzutifan (MK-6482) in Participants With Advanced Renal Cell Carcinoma (MK-6482-013) |
| NCT04626479 | PHASE1/PHASE2 | ACTIVE_NOT_RECRUITING | Substudy 03A: A Study of Immune and Targeted Combination Therapies in Participants With First Line (1L) Renal Cell Carcinoma (MK-3475-03A) |
| NCT04626518 | PHASE1/PHASE2 | ACTIVE_NOT_RECRUITING | Substudy 03B: A Study of Immune and Targeted Combination Therapies in Participants With Second Line Plus (2L+) Renal Cell Carcinoma (MK-3475-03B/KEYMAKER-U03) |
| NCT04924075 | PHASE2 | RECRUITING | 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) |
| NCT04976634 | PHASE2 | ACTIVE_NOT_RECRUITING | Pembrolizumab Plus Lenvatinib in Combination With Belzutifan in Solid Tumors (MK-6482-016) |
| NCT05468697 | PHASE1/PHASE2 | ACTIVE_NOT_RECRUITING | A Study of Belzutifan (MK-6482) in Combination With Palbociclib Versus Belzutifan Monotherapy in Participants With Advanced Renal Cell Carcinoma (MK-6482-024/LITESPARK-024) |
| NCT06428396 | PHASE2 | RECRUITING | Study of Belzutifan (MK-6482) Plus Fulvestrant for ER+/HER2- Metastatic Breast Cancer (MK-6482-029/LITESPARK-029) |
| NCT06677190 | PHASE2 | RECRUITING | Belzutifan in Recurrent Clear Cell Carcinoma of Gynecologic Origin |
| NCT07023432 | PHASE2 | RECRUITING | Belzutifan’s Role in Active Surveillance Versus Treatment for Indolentmetastatic Clear Cell Renal Ccell Carcinoma (BRAVE-RCC) |
| NCT07049926 | PHASE1/PHASE2 | RECRUITING | Substudy 03C: A Study of Combination Therapies in Participants With Renal Cell Carcinoma With Recurrent Disease During or After Anti-PD-(L)1 Therapy (MK-3475-03C/KEYMAKER-U03) |
| NCT07167329 | PHASE2 | RECRUITING | Real-World Effectiveness and Pharmacogenetics of Belzutifan in VHL Syndrome: The BELIEVE-VHL Trial |
| NCT07187778 | PHASE2 | RECRUITING | Phase II Trial of Single Agent Belzutifan or Pembrolizumab Versus Combination as Neoadjuvant Therapy in Clear Cell Renal Cell Carcinoma (BLAZE) |
| NCT07593040 | PHASE2 | NOT_YET_RECRUITING | Pembrolizumab Plus Belzutifan With or Without Lenvatinib in Localized Renal Cell Carcinoma |
| NCT02974738 | PHASE1 | ACTIVE_NOT_RECRUITING | A Trial of Belzutifan (PT2977, MK-6482) Tablets In Patients With Advanced Solid Tumors (MK-6482-001) |
| NCT05030506 | PHASE1 | ACTIVE_NOT_RECRUITING | A Study of Belzutifan (MK-6482) as Monotherapy and in Combination With Lenvatinib (E7080/MK-7902) With or Without Pembrolizumab (MK-3475) in China Participants With Advanced Renal Cell Carcinoma (MK-6482-010) |
| NCT06234605 | PHASE1 | RECRUITING | A Study of HC-7366 in Combination With Belzutifan (WELIREG™) in Patients With Renal Cell Carcinoma |
| NCT07179770 | PHASE1 | RECRUITING | Effects of Belzutifan on 89Zr-DFO-girentuximab PET Uptake in Patients With Renal Cell Carcinoma (RCC) |
| NCT03445169 | PHASE1 | COMPLETED | A Food Effect Study in Healthy Volunteers With Belzutifan (PT2977, MK-6482) Tablets |
| NCT04627064 | PHASE1 | COMPLETED | ABEMA Alone or in COMBO With MK-6482 |
| NCT04846920 | PHASE1 | COMPLETED | A Study of Belzutifan (MK-6482) in Participants With Advanced Clear Cell Renal Cell Carcinoma (MK-6482-018) |
| NCT04994522 | PHASE1 | COMPLETED | A Study of Belzutifan (MK-6482) in Participants With Renal Impairment (MK-6482-021) |
| NCT04995484 | PHASE1 | COMPLETED | A Study of Belzutifan (MK-6482) in Participants With Hepatic Impairment (MK-6482-020) |
| NCT06903715 | PHASE1 | COMPLETED | A Clinical Study of Belzutifan (MK-6482) Alone or With Phenytoin in Healthy Participants (CA46602/MK-6482-035) |
| NCT07121959 | PHASE1 | COMPLETED | A Study of Belzutifan (MK-6482) and Metformin in Healthy Adult Participants (MK-6482-039) |
| NCT06554730 | Not specified | WITHDRAWN | MSD Belzutifan PAS |
Clinical evidence (CIViC)
Variant × indication × effect (1 predictive associations from 1 curated evidence items):
| Variant | Indication | Effect | Therapy | Level | CIViC |
|---|---|---|---|---|---|
| EPAS1 Overexpression | Von Hippel-Lindau Disease | Sensitivity/Response | Belzutifan | CIViC B | EID12948 |
Pharmacology
Pharmacogenomics
No CPIC/DPWG dosing guideline, but PharmGKB curates 0 clinical and 4 variant annotation(s) for this drug (gene-keyed; see PharmGKB).
Related molecules
Related molecules
Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.
6 molecules share ≥1 primary target. Top 6 by shared-target count:
| Molecule | Source | Status | Shared targets |
|---|---|---|---|
| DOXORUBICIN | ChEMBL + PubChem | Phase 4 (approved) | EPAS1 |
| EMETINE | ChEMBL | Phase 4 (approved) | EPAS1 |
| TOPOTECAN | ChEMBL | Phase 4 (approved) | EPAS1 |
| ALVESPIMYCIN | ChEMBL | Phase 2 | EPAS1 |
| CYCLOHEXIMIDE | ChEMBL | Phase 2 | EPAS1 |
| Bortezomib | PubChem | Approved | EPAS1 |