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
Thumb
Weight
Average: 383.34
Monoisotopic: 383.043913533
Chemical Formula
C17H12F3NO4S
Synonyms
  • Belzutifan
External IDs
  • MK-6482
  • MK6482
  • PT 2977
  • PT-2977
  • PT2977
  • WHO 11196

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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
AEndothelial PAS domain-containing protein 1
inhibitor
Humans
Absorption

In patients with VHL disease-associated renal cell carcinoma, the mean Cmax and AUC0-24h 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 Tmax 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 Tmax 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
Adverseeffects
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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.
DrugInteraction
AbataceptThe metabolism of Belzutifan can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be decreased when it is combined with Belzutifan.
AbirateroneThe serum concentration of Belzutifan can be increased when it is combined with Abiraterone.
AcalabrutinibThe serum concentration of Acalabrutinib can be decreased when it is combined with Belzutifan.
AcenocoumarolThe serum concentration of Acenocoumarol can be decreased when it is combined with Belzutifan.
AdalimumabThe metabolism of Belzutifan can be increased when combined with Adalimumab.
AlbendazoleThe metabolism of Belzutifan can be decreased when combined with Albendazole.
AlectinibThe serum concentration of Alectinib can be decreased when it is combined with Belzutifan.
AlpelisibThe serum concentration of Alpelisib can be decreased when it is combined with Belzutifan.
AminophenazoneThe serum concentration of Belzutifan can be increased when it is combined with Aminophenazone.
Interactions
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Food Interactions
  • Take with or without food. The administration of food with belzutifan has no clinically meaningful effect on its disposition.

Products

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International/Other Brands
Welireg (Merck)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
WeliregTablet, film coated40 mg/1OralMerck Sharp & Dohme Corp.2021-08-13Not applicableUS flag

Categories

Drug Categories
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]
ChemSpider
59053536
BindingDB
373040
RxNav
2567226
ChEMBL
CHEMBL4585668
ZINC
ZINC000584905085
PDBe Ligand
72Q
Wikipedia
Belzutifan

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentRenal Cell Adenocarcinoma3
2Active Not RecruitingTreatmentVHL - Von Hippel-Lindau Syndrome / VHL Gene Inactivation / VHL Gene Mutation / VHL Syndrome / VHL-Associated Clear Cell Renal Cell Carcinoma / VHL-Associated Renal Cell Carcinoma1
2RecruitingTreatmentBiliary Tract Neoplasms / Hepatocellular Carcinoma / Neoplasms, Colorectal / Pancreatic Adenocarcinoma (Ductal Adenocarcinoma)1
2RecruitingTreatmentClear Cell Renal Cell Carcinoma (ccRCC) / Kidney / Renal Cancers / Renal Cell Adenocarcinoma / Renal Cell Cancer Metastatic / Renal Cell Cancer, Recurrent / Renal Cell Carcinoma Recurrent1
2RecruitingTreatmentPheochromocytoma/Paraganglioma / Progressive Neuroendocrine Tumors of pancreatic origin1
2RecruitingTreatmentRenal Cell Adenocarcinoma1
1Active Not RecruitingTreatmentCcRCC / Clear Cell Renal Cell Carcinoma (ccRCC) / GBM / Glioblastoma Multiforme (GBM) / Glioblastoma, Adult / Metastatic Renal Cell Carcinoma ( mRCC) / RCC / RCC, Clear Cell Adenocarcinoma / Renal Cancers / Renal Cell Carcinoma Recurrent / Renal Cell Carcinoma, Clear Cell Adenocarcinoma / Solid Carcinoma / Solid Tumors, Adult / Solid Tumors, Advanced Solid Tumors / Tumors, Solid1
1CompletedTreatmentHealthy Subjects (HS)1
1Not Yet RecruitingTreatmentDeteriorating renal function / End Stage Renal Disease (ESRD)1
1Not Yet RecruitingTreatmentModerate Hepatic Impairment1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral40 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsolublehttps://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215383s000lbl.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.0794 mg/mLALOGPS
logP2.49ALOGPS
logP1.88ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)12.53ChemAxon
pKa (Strongest Basic)-3.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area87.39 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity85.82 m3·mol-1ChemAxon
Polarizability33.2 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Glucuronosyltransferase activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. The major substrates of this isozyme are eugenol > 4-methylumbe...
Gene Name
UGT2B17
Uniprot ID
O75795
Uniprot Name
UDP-glucuronosyltransferase 2B17
Molecular Weight
61094.915 Da
References
  1. FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Drug transmembrane transporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
Gene Name
SLC47A2
Uniprot ID
Q86VL8
Uniprot Name
Multidrug and toxin extrusion protein 2
Molecular Weight
65083.915 Da
References
  1. FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]

Drug created on May 21, 2019 17:13 / Updated on August 28, 2021 08:41