Belzutifan

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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

Similar Structures

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	Approval Level	Age Group	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	••••••••••••	•••••	••••••

Contraindications & Blackbox Warnings

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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.

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.

Products

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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

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

FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]
FDA News Release: FDA approves belzutifan for cancers associated with von Hippel-Lindau disease [Link]
VHL Alliance: Belzutifan (Welireg; MK-6482; PT-2977) and VHL Disease [Link]
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]
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

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Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
Unlock 175K+ rows when you subscribe.View sample data
3	Active Not Recruiting	Treatment	Renal Cell Carcinoma (RCC)	5	somestatus	stop reason	just information to hide
2	Active Not Recruiting	Treatment	Clear Cell Renal Cell Carcinoma / Kidneys / Metastatic Renal Cell Carcinoma ( mRCC) / Recurrent Renal Cell Cancer / Renal Cancer / Renal Cell Carcinoma (RCC) / Renal Cell Carcinoma Recurrent	1	somestatus	stop reason	just information to hide
2	Active Not Recruiting	Treatment	Renal Cell Carcinoma (RCC)	1	somestatus	stop reason	just information to hide
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	somestatus	stop reason	just information to hide
2	Not Yet Recruiting	Treatment	Metastatic Breast Cancer	1	somestatus	stop reason	just information to hide

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)
US9908845	No	2018-03-06	2034-09-05
US9969689	No	2018-05-15	2034-09-05
USRE49948	No	2014-09-05	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 APEX1 seems to activate CTAD (By similarity)
Specific Function: Dna-binding transcription activator activity, rna polymerase ii-specific
Gene Name: EPAS1
Uniprot ID: Q99814
Uniprot Name: Endothelial PAS domain-containing protein 1
Molecular Weight: 96458.235 Da

References

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]
Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]

Enzymes

Details1. UDP-glucuronosyltransferase 2B17

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: UDP-glucuronosyltransferase (UGT) that catalyzes phase II biotransformation reactions in which lipophilic substrates are conjugated with glucuronic acid to increase the metabolite's water solubility, thereby facilitating excretion into either the urine or bile (PubMed:16595710, PubMed:18719240, PubMed:19022937, PubMed:23288867, PubMed:8798464). Catalyzes the glucuronidation of endogenous steroid hormones such as androgens (epitestosterone, androsterone) and estrogens (estradiol, epiestradiol) (PubMed:16595710, PubMed:18719240, PubMed:19022937, PubMed:23288867, PubMed:8798464)
Specific Function: Glucuronosyltransferase activity
Gene Name: UGT2B17
Uniprot ID: O75795
Uniprot Name: UDP-glucuronosyltransferase 2B17
Molecular Weight: 61094.915 Da

References

FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]

Details2. Cytochrome P450 2C19

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:19965576, PubMed:20972997). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). 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 imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307)
Specific Function: (r)-limonene 6-monooxygenase activity
Gene Name: CYP2C19
Uniprot ID: P33261
Uniprot Name: Cytochrome P450 2C19
Molecular Weight: 55944.565 Da

References

FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]

Details3. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function: 1,8-cineole 2-exo-monooxygenase activity
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]

Transporters

Details1. ATP-dependent translocase ABCB1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function: Abc-type xenobiotic transporter activity
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: ATP-dependent translocase ABCB1
Molecular Weight: 141477.255 Da

References

FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]

Details2. Solute carrier organic anion transporter family member 1B1

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
Specific Function: Bile acid transmembrane transporter activity
Gene Name: SLCO1B1
Uniprot ID: Q9Y6L6
Uniprot Name: Solute carrier organic anion transporter family member 1B1
Molecular Weight: 76447.99 Da

References

FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]

Details3. Solute carrier organic anion transporter family member 1B3

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Substrate

General Function: Mediates the Na(+)-independent uptake of organic anions (PubMed:10779507, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (17-beta-glucuronosyl estradiol, dehydroepiandrosterone sulfate (DHEAS), and estrone 3-sulfate), as well as eicosanoid leukotriene C4, prostaglandin E2 and L-thyroxine (T4) (PubMed:10779507, PubMed:11159893, PubMed:12568656, PubMed:15159445, PubMed:17412826, PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). Shows a pH-sensitive substrate specificity towards sulfated steroids, taurocholate and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Involved in the clearance of bile acids and organic anions from the liver (PubMed:22232210). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins) such as pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:15159445). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748)
Specific Function: Bile acid transmembrane transporter activity
Gene Name: SLCO1B3
Uniprot ID: Q9NPD5
Uniprot Name: Solute carrier organic anion transporter family member 1B3
Molecular Weight: 77402.175 Da

References

FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]

Details4. Multidrug and toxin extrusion protein 2

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inhibitor

General Function: Multidrug efflux pump that functions as a H(+)/organic cation antiporter. Mediates the efflux of cationic compounds, such as the model cations, tetraethylammonium (TEA) and 1-methyl-4-phenylpyridinium (MPP+), the platinum-based drug oxaliplatin or weak bases that are positively charged at physiological pH, cimetidine, the platinum-based drugs cisplatin and oxaliplatin or the antidiabetic drug metformin. Mediates the efflux of endogenous compounds such as, creatinine, thiamine and estrone-3-sulfate. Plays a physiological role in the excretion of drugs, toxins and endogenous metabolites through the kidney
Specific Function: Antiporter activity
Gene Name: SLC47A2
Uniprot ID: Q86VL8
Uniprot Name: Multidrug and toxin extrusion protein 2
Molecular Weight: 65083.915 Da

References

FDA Approved Drug Products: Welireg (belzutifan) tablets for oral use [Link]

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

Belzutifan

Identification

Structure for Belzutifan (DB15463)

Pharmacology

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Chemical Identifiers

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Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

Pharmacoeconomics

Properties

Spectra

Collision Cross Sections (CCS)

Targets

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Enzymes

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Transporters

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