Belzutifan

Identification

Summary

Belzutifan is an inhibitor of hypoxia-inducible factor 2α used as an antineoplastic in the treatment of certain cancers associated with von Hippel-Lindau (VHL) disease.

Brand Names

Welireg

Generic Name

Belzutifan

DrugBank Accession Number

DB15463

Background

Belzutifan is an inhibitor of hypoxia-inducible factor 2α (HIF-2α) used in the treatment of von Hippel-Lindau (VHL) disease-associated cancers.¹ The HIF-2α protein was first identified in the 1990s by researchers at UT Southwestern Medical Center as a key player in the growth of certain cancers.⁴ Initially considered to be undruggable, a binding pocket was eventually discovered in the HIF-2α molecule which allowed for compounds to bind and inhibit these proteins. This discovery led to the initial development of belzutifan (at the time called PT2977), which was further developed by a spin-off company named Peloton Pharmaceuticals (which itself was eventually acquired by Merck in 2019).⁴

Belzutifan inhibits the complexation of HIF-2α with another transcription factor, HIF-1β, a necessary step in its activation - by preventing the formation of this complex, belzutifan can slow or stop the growth of VHL-associated tumors. Belzutifan received FDA approval for the treatment of select VHL-associated cancers on August 13, 2021.²

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Belzutifan (DB15463)

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Weight

Average: 383.34
Monoisotopic: 383.043913533

Chemical Formula

C₁₇H₁₂F₃NO₄S

Synonyms

• Belzutifan

External IDs

• MK-6482
• MK6482
• PT 2977
• PT-2977
• PT2977
• WHO 11196

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Pharmacology

Indication

Belzutifan is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), who do not require immediate surgery.¹

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Adjunct therapy in treatment of	Advanced renal cell carcinoma		••••••••••••	•••••		••••••
Adjunct therapy in treatment of	Advanced renal cell carcinoma		••••••••••••	•••••		••••••
Treatment of	Hemangioblastoma (hb) of the central nervous system (cns)		••••••••••••	•••••		••••••
Treatment of	Pancreatic neuroendocrine cancer		••••••••••••	•••••		••••••
Treatment of	Renal cell adenocarcinoma		••••••••••••	•••••		••••••

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Pharmacodynamics

Belzutifan exerts its therapeutic effects by inhibiting a transcription factor necessary for the growth of solid tumors associated with VHL disease.¹ It is taken once daily at approximately the same time each day, with or without food. Both severe anemia and hypoxia have been observed following therapy with belzutifan, and patients should be monitored closely before and during therapy to ensure patients can be managed as clinically indicated. There are no data regarding the use of erythropoiesis-stimulating agents for the treatment of belzutifan-induced anemia, and as such these therapies should be avoided.¹

Belzutifan may cause embryo-fetal toxicity when administered to pregnant women. Female patients and male patients with female partners of reproductive potential should ensure that an effective form of contraception is used throughout therapy and for one week after the last dose - as belzutifan appears to decrease the efficacy of systemic hormonal contraceptives, patients should be advised to use an additional method of contraception (e.g. condoms) to eliminate the possibility of pregnancy during therapy.¹

Mechanism of action

Hypoxia-inducible factor 2α (HIF-2α) is a transcription factor which aids in oxygen sensing by regulating genes that promote adaptation to hypoxia.¹ In healthy patients, when oxygen levels are normal, HIF-2α is broken down via ubiquitin-proteasomal degradation by von-Hippel Lindau (VHL) proteins. In the presence of hypoxia, HIF-2α translocates into cell nuclei and forms a transcriptional complex with hypoxia-inducible factor 1β (HIF-1β) - this complex then induces the expression of downstream genes associated with cellular proliferation and angiogenesis.¹

Patients with von-Hippel Lindau (VHL) disease lack functional VHL proteins, leading to an accumulation of HIF-2α, and this accumulation is what drives the growth of VHL-associated tumors. Belzutifan is an inhibitor of HIF-2α that prevents its complexation with HIF-1β in conditions of hypoxia or impaired VHL protein function, thereby reducing the expression of HIF-2α target genes and slowing/stopping the growth of VHL-associated tumors.¹

Target	Actions	Organism
AEndothelial PAS domain-containing protein 1	inhibitor	Humans

Absorption

In patients with VHL disease-associated renal cell carcinoma, the mean C_max and AUC_0-24h at steady-state - which was achieved after approximately three days of therapy - were 1.3 µg/mL and 16.7 μg•hr/mL, respectively.¹ The median T_max is one to two hours following oral administration.¹

The administration of belzutifan with food has a negligible effect on drug disposition - when given alongside a high-calorie, high-fat meal, the T_max was delayed by approximately 2 hours with no other clinically meaningful effects observed.¹

Volume of distribution

The steady-state volume of distribution of belzutifan following oral administration is approximately 130 L.¹

Protein binding

Plasma protein-binding is approximately 45%, although data regarding the specific proteins to which belzutifan binds are unavailable.¹

Metabolism

Belzutifan is primarily metabolized by UGT2B17 and CYP2C19, and to a lesser extent by CYP3A4.¹

Route of elimination

Not Available

Half-life

The mean elimination half-life of belzutifan is 14 hours.¹

Clearance

The mean clearance of belzutifan following oral administration is 7.3 L/h.¹

Adverse Effects

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Toxicity

Data regarding overdosage with belzutifan is lacking. There is no specific treatment available for belzutifan overdose - if a patient is suspected to have overdosed, immediately withhold belzutifan and institute standard supportive care. Grade 3 hypoxia has been observed at doses of 120mg twice daily and Grade 4 thrombocytopenia has been observed at doses of 240mg once daily (twice the recommended dose).¹

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abatacept	The metabolism of Belzutifan can be increased when combined with Abatacept.
Abemaciclib	The serum concentration of Abemaciclib can be decreased when it is combined with Belzutifan.
Abiraterone	The serum concentration of Belzutifan can be increased when it is combined with Abiraterone.
Abrocitinib	The metabolism of Belzutifan can be decreased when combined with Abrocitinib.
Acalabrutinib	The serum concentration of Acalabrutinib can be decreased when it is combined with Belzutifan.

Food Interactions

• Take with or without food. The administration of food with belzutifan has no clinically meaningful effect on its disposition.

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International/Other Brands

Welireg (Merck)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Welireg	Tablet	40 mg	Oral	Merck Ltd.	2022-09-01	Not applicable
Welireg	Tablet, film coated	40 mg/1	Oral	Merck Sharp & Dohme LLC	2021-08-13	Not applicable

Categories

ATC Codes

L01XX74 — Belzutifan

• L01XX — Other antineoplastic agents
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Hypoxia-inducible Factor Inhibitor
• MATE 2 Inhibitors
• MATE inhibitors
• OATP1B1/SLCO1B1 Substrates
• OATP1B3 substrates
• P-glycoprotein substrates
• UGT2B17 substrates

Classification

Not classified

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

7K28NB895L

CAS number

1672668-24-4

InChI Key

LOMMPXLFBTZENJ-ZACQAIPSSA-N

InChI

InChI=1S/C17H12F3NO4S/c1-26(23,24)12-3-2-11(13-14(12)17(22)16(20)15(13)19)25-10-5-8(7-21)4-9(18)6-10/h2-6,15-17,22H,1H3/t15-,16-,17+/m1/s1

IUPAC Name

3-{[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methanesulfonyl-2,3-dihydro-1H-inden-4-yl]oxy}-5-fluorobenzonitrile

SMILES

CS(=O)(=O)C1=CC=C(OC2=CC(=CC(F)=C2)C#N)C2=C1[C@H](O)[C@H](F)[C@@H]2F

References

Synthesis Reference

Xu R, Wang K, Rizzi JP, Huang H, Grina JA, Schlachter ST, Wang B, Wehn PM, Yang H, Dixon DD, Czerwinski RM, Du X, Ged EL, Han G, Tan H, Wong T, Xie S, Josey JA, Wallace EM: 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzo nitrile (PT2977), a Hypoxia-Inducible Factor 2alpha (HIF-2alpha) Inhibitor for the Treatment of Clear Cell Renal Cell Carcinoma. J Med Chem. 2019 Aug 8;62(15):6876-6893. doi: 10.1021/acs.jmedchem.9b00719. Epub 2019 Jul 8.

General References

1. FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]
2. FDA News Release: FDA approves belzutifan for cancers associated with von Hippel-Lindau disease [Link]
3. VHL Alliance: Belzutifan (Welireg; MK-6482; PT-2977) and VHL Disease [Link]
4. UT Southwestern Medical Center News Release: FDA approval of belzutifan culminates 25-year journey at UTSW from gene discovery to a first-in-class drug [Link]
5. FDA Approved Drug Products: WELIREG® (belzutifan) tablets, for oral use (Dec 2023) [Link]

External Links

Human Metabolome Database

HMDB0304835

ChemSpider

59053536

BindingDB

373040

RxNav

2567226

ChEMBL

CHEMBL4585668

ZINC

ZINC000584905085

PharmGKB

PA166268761

PDBe Ligand

72Q

Wikipedia

Belzutifan

PDB Entries

7w80

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Active Not Recruiting	Treatment	Renal Cell Carcinoma (RCC)	4
3	Recruiting	Treatment	Renal Cell Carcinoma (RCC)	1
2	Active Not Recruiting	Treatment	Clear Cell Renal Cell Carcinoma / Kidney / Metastatic Renal Cell Carcinoma ( mRCC) / Recurrent Renal Cell Cancer / Renal Cancer / Renal Cell Carcinoma (RCC) / Renal Cell Carcinoma Recurrent	1
2	Active Not Recruiting	Treatment	Renal Cell Carcinoma (RCC)	1
2	Active Not Recruiting	Treatment	VHL Gene Inactivation / VHL Gene Mutation / VHL Syndrome / VHL-Associated Clear Cell Renal Cell Carcinoma / VHL-Associated Renal Cell Carcinoma / Von Hippel-Lindau Disease	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	40 mg
Tablet, film coated	Oral	40 mg/1

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9908845	No	2018-03-06	2034-09-05
US9969689	No	2018-05-15	2034-09-05

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Insoluble	https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215383s000lbl.pdf

Predicted Properties

Property	Value	Source
Water Solubility	0.0794 mg/mL	ALOGPS
logP	2.49	ALOGPS
logP	1.88	Chemaxon
logS	-3.7	ALOGPS
pKa (Strongest Acidic)	12.53	Chemaxon
pKa (Strongest Basic)	-3.7	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	87.39 Å2	Chemaxon
Rotatable Bond Count	3	Chemaxon
Refractivity	85.82 m3·mol-1	Chemaxon
Polarizability	33.2 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-001i-0009000000-29e000e0b8cd0c7835f3
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-01q9-0009000000-3cb0d689fc49bbcf4206
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-001i-0009000000-307b63e0ee2919660586
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0059-7109000000-3f7080f2c5cc91de5497
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00e9-0039000000-0e507f20ed59636423fc
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-00n0-9142000000-5967897fbb317906bdb3
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Endothelial PAS domain-containing protein 1

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Inhibitor

General Function

Transcription factor involved in the induction of oxygen regulated genes. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBBP and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD (By similarity).

Specific Function

Dna binding

Gene Name

EPAS1

Uniprot ID

Q99814

Uniprot Name

Endothelial PAS domain-containing protein 1

Molecular Weight

96458.235 Da

References

1. Tai W. Wong, Rajeev Shrimali, Cristina Contreras, Tzuling Cheng, Robert M. Czerwinski, Daryl D. Dixon, Xinlin Du, Craig Fett, Jessica Goree, Jonas A. Grina, Guangzhou Han, Heli Huang, Jim Rizzi, Stephen T. Schlachter, Bin Wang, Keshi Wang, Paul M. Wehn, Shanhai Xie, Rui Xu, Hanbiao Yang, John A. Josey and Eli M. Wallace: Abstract B140: PT2977, a novel HIF-2a antagonist, has potent antitumor activity and remodels the immunosuppressive tumor microenvironment in clear cell renal cell cancer AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics. [Article]
2. FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]

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Drug created at May 21, 2019 17:13 / Updated at December 15, 2023 23:52