Belumosudil
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Identification
- Summary
Belumosudil is an oral inhibitor of rho-associated coiled-coil-containing protein kinases (ROCK) used in the treatment of chronic graft-versus-host disease (GVHD).
- Brand Names
- Rezurock
- Generic Name
- Belumosudil
- DrugBank Accession Number
- DB16703
- Background
Belumosudil is used in the treatment of chronic graft-versus-host disease (GVHD) and has been investigated for the treatment of pulmonary arterial hypertension.4 It is an inhibitor of rho-associated coiled-coil-containing protein kinases (ROCK), with significantly more selectivity for ROCK2 as compared to ROCK1 (IC50 100 nM vs. 3 μM, respectively).5 In the treatment of GVHD, a condition in which donor T-cells begin to attack recipient tissues following allogeneic hematopoeitic stem cell transplantation (HSCT), belumosudil helps to resolve immune dysregulation by shifting the balance between Th17 cells and T-regulatory cells, thereby dampening the inflammatory cascade that can occasionally be fatal.3,7
Belumosudil was first approved by the FDA in July 2021, under the brand name Rezurock, for the treatment of chronic GVHD in patients who have tried and failed at least two prior lines of systemic therapy.6 In July 2022, Belumosudil was approved by Health Canada under the brand name RHOLISTIQ to treat the same condition in adult and pediatric patients 12 years or older.10
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 452.518
Monoisotopic: 452.196074037 - Chemical Formula
- C26H24N6O2
- Synonyms
- Belumosudil
- External IDs
- BN101
- KD-025
- KD025
- SLx-2119
- WHO 11343
Pharmacology
- Indication
Belumosudil is indicated for the treatment of chronic graft-versus-host disease (GVHD) in adult and pediatric patients 12 years of age and older following failure of at least two other lines of systemic therapy.5
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Chronic graft-versus-host disease •••••••••••• •••••• ••••••••• ••• ••••• •••••••• ••••••••• •••••• Treatment of Chronic graft-versus-host disease •••••••••••• •• ••••• ••• ••••• •••••••• ••••••••• •••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
Belumosudil appears to inhibit several pro-fibrotic and pro-inflammatory processes in order to prevent and treat the damage incurred by graft-versus-host disease. Given its mechanism of action and findings in animal trials, belumosudil is considered to carry embryo-fetal toxicity and may cause significant harm to a developing fetus should a pregnant mother be exposed.5 Female patients of reproductive potential, or male patients with female partners of reproductive potential, should be advised to use effective contraception during treatment with belumosudil and for one week after the last dose.5
- Mechanism of action
Chronic graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation in which the transplanted donor T-cells recognize the recipient's tissues as foreign and mount an immune response.2 During the conditioning regimen prior to stem cell transplantation (e.g. involving irradiation or chemotherapy) the host tissues can become damaged which results in downstream inflammatory responses and the generation of inflammatory mediators like TNF-alpha and IL-1. These cytokines increase the expression of host major histocompatibility (MHC) antigens and adhesion molecules which enhances the ability of mature donor T-cells to recognize these molecules. The activation of these donor T-cells results in the activation of mononuclear phagocytes, whose effector functions are triggered by stimulatory molecules generated by the damage incurred during the conditioning phase of treatment. Activated macrophages and cytotoxic T-lymphocytes begin to directly lyse target cells and/or cause their apoptosis, which eventually leads to local tissue damage and further inflammatory responses.3
Belumosudil is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2), a protein that plays a vital role in the pathogenesis of immune and fibrotic diseases. The inhibition of ROCK2 has been shown to resolve immune dysregulation by down-regulating pro-inflammatory Th17 cells and up-regulating regulatory T-cells by manipulating the phosphorylation of STAT3 and STAT5.5,7
Target Actions Organism ARho-associated protein kinase 2 inhibitorHumans ARho-associated protein kinase 1 inhibitorHumans - Absorption
Following oral administration, the mean bioavailability of belumosudil is 64% and the median Tmax at steady-state is 1.26 to 2.53 hours.5 As compared to administration in a fasted state, belumosudil Cmax and AUC increased by 2.2 and 2 times, respectively, when administered with a high-fat, high-calorie meal.5
- Volume of distribution
Following a single oral dose of belumosudil in healthy subjects, the mean geometric volume of distribution was 184 L.5
- Protein binding
Belumosudil appears to be extensively protein-bound in plasma - in vitro protein binding to serum albumin and alpha-1-acid glycoprotein was found to be 99.9% and 98.6%, respectively.5
- Metabolism
The in vitro metabolism of belumosudil occurs primarily via CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and UGT1A9.5 The specific metabolites generated by belumosudil metabolism remain unclear.
- Route of elimination
Belumosudil is eliminated primarily in the feces. Following the administration of a radiolabeled oral dose of belumosudil in healthy subjects, approximately 85% of the radioactivity was recovered in the feces, 30% of which was unchanged parent drug, with less than 5% recovered in the urine.5
- Half-life
The mean elimination half-life of belumosudil following oral administration is 19 hours.5
- Clearance
The mean clearance of belumosudil is 9.83 L/h.5
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
There are no data regarding overdosage with belumosudil.
- 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 Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Belumosudil can be increased when it is combined with Abametapir. Abatacept The risk or severity of adverse effects can be increased when Abatacept is combined with Belumosudil. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Belumosudil. Adalimumab The risk or severity of adverse effects can be increased when Adalimumab is combined with Belumosudil. Adenovirus type 7 vaccine live The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Belumosudil. - Food Interactions
- Take at the same time every day. Belumosudil should be taken with a meal at approximately the same time each day.
- Take with food. The co-administration of food increases the absorption of belumosudil.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Belumosudil mesylate 6MX7XE1M0U 2109704-99-4 BGNMZPDNJWWQCU-UHFFFAOYSA-N Belumosudil trifluoroacetate LL4OG4RZ5D 1243152-02-4 PBWWPJDQYJXRII-UHFFFAOYSA-N - International/Other Brands
- Rezurock (Kadmon Holdings, Inc.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Rezurock Tablet 200 mg/1 Oral Kadmon Pharmaceuticals, LLC 2021-07-16 Not applicable US Rezurock Tablet 200 mg/1 Oral Pharma Packaging Solutions, LLC dba Tjoapack LLC 2021-07-16 Not applicable US Rezurock Tablet 200 mg Oral Sanofi Aventis Deutschland Gmb H 2023-03-08 Not applicable Canada
Categories
- ATC Codes
- L04AA48 — Belumosudil
- Drug Categories
- Acetates
- Acids, Acyclic
- Amides
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Inhibitors
- Cytochrome P-450 CYP1A2 Inhibitors
- Cytochrome P-450 CYP1A2 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C19 inhibitors (strength unknown)
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2D6 Inhibitors
- Cytochrome P-450 CYP2D6 Inhibitors (strength unknown)
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P-450 Substrates
- Enzyme Inhibitors
- Heterocyclic Compounds, Fused-Ring
- Immunosuppressive Agents
- OATP1B1/SLCO1B1 Inhibitors
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- Protein Kinase Inhibitors
- Selective Immunosuppressants
- UGT1A1 Inhibitors
- UGT1A9 Inhibitors
- UGT1A9 Substrates
- Classification
- Not classified
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 834YJF89WO
- CAS number
- 911417-87-3
- InChI Key
- GKHIVNAUVKXIIY-UHFFFAOYSA-N
- InChI
- InChI=1S/C26H24N6O2/c1-16(2)28-24(33)15-34-20-7-5-6-17(13-20)25-30-23-9-4-3-8-21(23)26(31-25)29-19-10-11-22-18(12-19)14-27-32-22/h3-14,16H,15H2,1-2H3,(H,27,32)(H,28,33)(H,29,30,31)
- IUPAC Name
- 2-(3-{4-[(1H-indazol-5-yl)amino]quinazolin-2-yl}phenoxy)-N-(propan-2-yl)acetamide
- SMILES
- CC(C)NC(=O)COC1=CC=CC(=C1)C1=NC2=C(C=CC=C2)C(NC2=CC=C3NN=CC3=C2)=N1
References
- Synthesis Reference
殷燕, 孙玉星, 张华, 孙国峰, 陶瑞衡, 段永斌, 孙越, and 江沁楠. The Synthetic Method of SLx 2119. SHANGHAI SCIENPHARM BIOTECHNOLOGY Co.,Ltd., assignee. Patent CN106916145A. 4 June 2019.
- General References
- Cutler CS, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, Ramakrishnan A, DeFilipp Z, Salhotra A, Chai-Ho W, Mehta RS, Wang T, Arora M, Pusic I, Saad A, Shah NN, Abhyankar S, Bachier C, Galvin JP, Im A, Langston A, Liesveld JL, Juckett M, Logan A, Schachter L, Alavi A, Howard DS, Waksal H, Ryan J, Eiznhamer D, Aggarwal SK, Ieyoub J, Schueller O, Green LS, Yang Z, Krenz H, Jagasia M, Blazar BR, Pavletic SZ: Belumosudil for Chronic Graft-versus-Host Disease (cGVHD) After 2 or More Prior Lines of Therapy: The ROCKstar Study. Blood. 2021 Jul 15. pii: 476399. doi: 10.1182/blood.2021012021. [Article]
- Braun LM, Zeiser R: Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease. Hemasphere. 2021 Jun 1;5(6):e581. doi: 10.1097/HS9.0000000000000581. eCollection 2021 Jun. [Article]
- Ferrara JL, Reddy P: Pathophysiology of graft-versus-host disease. Semin Hematol. 2006 Jan;43(1):3-10. doi: 10.1053/j.seminhematol.2005.09.001. [Article]
- Yamamura A, Nayeem MJ, Sato M: The Rho kinase 2 (ROCK2)-specific inhibitor KD025 ameliorates the development of pulmonary arterial hypertension. Biochem Biophys Res Commun. 2021 Jan 1;534:795-801. doi: 10.1016/j.bbrc.2020.10.106. Epub 2020 Nov 5. [Article]
- FDA Approved Drug Products: Rezurock (belumosudil) tablets for oral use [Link]
- FDA News Release: FDA approves belumosudil for chronic graft-versus-host disease [Link]
- Kadmon: Belumosudil Mechanism of Action [Link]
- MedChemExpress: Belumosudil Safety Data Sheet [Link]
- Health Canada Approved Drug Proucts: RHOLISTIQ (Belumosudil) tablet for oral use [Link]
- Health Canada News Release: Health Canada approves belumosudil for chronic graft-versus-host disease [Link]
- External Links
- Human Metabolome Database
- HMDB0247641
- KEGG Drug
- D11815
- ChemSpider
- 10124479
- BindingDB
- 322155
- 2564025
- ChEMBL
- CHEMBL2005186
- ZINC
- ZINC000063298464
- PDBe Ligand
- ICQ
- Wikipedia
- Belumosudil
- PDB Entries
- 7z39
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Recruiting Treatment Safety Issues 1 somestatus stop reason just information to hide 4 Not Yet Recruiting Treatment Chronic Graft-Versus-Host Disease 1 somestatus stop reason just information to hide 3 Recruiting Treatment Chronic Graft-Versus-Host Disease 1 somestatus stop reason just information to hide 3 Recruiting Treatment Lung Transplant Rejection 1 somestatus stop reason just information to hide 2 Completed Treatment Chronic Graft-Versus-Host Disease 2 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral 200 mg/1 Tablet Oral 200 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US10696660 No 2020-06-30 2033-10-07 US US10183931 No 2019-01-22 2033-10-07 US US9815820 No 2017-11-14 2033-10-07 US US8357693 No 2013-01-22 2029-10-30 US US11311541 No 2015-04-09 2035-04-09 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source boiling point (°C) 682.6±55.0 https://file.medchemexpress.com/batch_PDF/HY-15307/Belumosudil-SDS-MedChemExpress.pdf water solubility Practically insoluble https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214783s000lbl.pdf - Predicted Properties
Property Value Source Water Solubility 0.00289 mg/mL ALOGPS logP 4.65 ALOGPS logP 4.65 Chemaxon logS -5.2 ALOGPS pKa (Strongest Acidic) 13.08 Chemaxon pKa (Strongest Basic) 4.11 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 104.82 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 141.46 m3·mol-1 Chemaxon Polarizability 49.55 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes 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 splash10-0udi-3202900000-4bf7c16e5a8dff9c735f Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0udl-9008200000-604c6acda59190e36777 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0udl-1009400000-9726f355b56f1083e69e Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0udi-6009100000-9f41f132a348f00f26c6 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0f6x-8009200000-052993a792c017ec4d34 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0udi-2049000000-8002047d898435abd8ba Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 241.63022 predictedDarkChem Lite v0.1.0 [M+H]+ 241.32422 predictedDarkChem Lite v0.1.0 [M+Na]+ 241.29102 predictedDarkChem Lite v0.1.0
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Protein kinase which is a key regulator of actin cytoskeleton and cell polarity. Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of ADD1, BRCA2, CNN1, EZR, DPYSL2, EP300, MSN, MYL9/MLC2, NPM1, RDX, PPP1R12A and VIM. Phosphorylates SORL1 and IRF4. Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation. Positively regulates the activation of p42/MAPK1-p44/MAPK3 and of p90RSK/RPS6KA1 during myogenic differentiation. Plays an important role in the timely initiation of centrosome duplication. Inhibits keratinocyte terminal differentiation. May regulate closure of the eyelids and ventral body wall through organization of actomyosin bundles. Plays a critical role in the regulation of spine and synaptic properties in the hippocampus. Plays an important role in generating the circadian rhythm of the aortic myofilament Ca(2+) sensitivity and vascular contractility by modulating the myosin light chain phosphorylation
- Specific Function
- ATP binding
- Gene Name
- ROCK2
- Uniprot ID
- O75116
- Uniprot Name
- Rho-associated protein kinase 2
- Molecular Weight
- 160898.555 Da
References
- Cutler CS, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, Ramakrishnan A, DeFilipp Z, Salhotra A, Chai-Ho W, Mehta RS, Wang T, Arora M, Pusic I, Saad A, Shah NN, Abhyankar S, Bachier C, Galvin JP, Im A, Langston A, Liesveld JL, Juckett M, Logan A, Schachter L, Alavi A, Howard DS, Waksal H, Ryan J, Eiznhamer D, Aggarwal SK, Ieyoub J, Schueller O, Green LS, Yang Z, Krenz H, Jagasia M, Blazar BR, Pavletic SZ: Belumosudil for Chronic Graft-versus-Host Disease (cGVHD) After 2 or More Prior Lines of Therapy: The ROCKstar Study. Blood. 2021 Jul 15. pii: 476399. doi: 10.1182/blood.2021012021. [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: Rezurock (belumosudil) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Protein kinase which is a key regulator of the actin cytoskeleton and cell polarity (PubMed:10436159, PubMed:10652353, PubMed:11018042, PubMed:11283607, PubMed:17158456, PubMed:18573880, PubMed:19131646, PubMed:8617235, PubMed:9722579). Involved in regulation of smooth muscle contraction, actin cytoskeleton organization, stress fiber and focal adhesion formation, neurite retraction, cell adhesion and motility via phosphorylation of DAPK3, GFAP, LIMK1, LIMK2, MYL9/MLC2, TPPP, PFN1 and PPP1R12A (PubMed:10436159, PubMed:10652353, PubMed:11018042, PubMed:11283607, PubMed:17158456, PubMed:18573880, PubMed:19131646, PubMed:23093407, PubMed:23355470, PubMed:8617235, PubMed:9722579). Phosphorylates FHOD1 and acts synergistically with it to promote SRC-dependent non-apoptotic plasma membrane blebbing (PubMed:18694941). Phosphorylates JIP3 and regulates the recruitment of JNK to JIP3 upon UVB-induced stress (PubMed:19036714). Acts as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability (By similarity). Acts as a negative regulator of VEGF-induced angiogenic endothelial cell activation (PubMed:19181962). Required for centrosome positioning and centrosome-dependent exit from mitosis (By similarity). Plays a role in terminal erythroid differentiation (PubMed:21072057). Inhibits podocyte motility via regulation of actin cytoskeletal dynamics and phosphorylation of CFL1 (By similarity). Promotes keratinocyte terminal differentiation (PubMed:19997641). Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process, essential for osteoblast mineralization (By similarity). May regulate closure of the eyelids and ventral body wall by inducing the assembly of actomyosin bundles (By similarity)
- Specific Function
- ATP binding
- Gene Name
- ROCK1
- Uniprot ID
- Q13464
- Uniprot Name
- Rho-associated protein kinase 1
- Molecular Weight
- 158173.545 Da
References
- FDA Approved Drug Products: Rezurock (belumosudil) tablets for oral use [Link]
Enzymes
- 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: Rezurock (belumosudil) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). 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:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576, PubMed:7574697). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:15766564, PubMed:19965576, PubMed:7574697). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316)
- Specific Function
- arachidonic acid epoxygenase activity
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- FDA Approved Drug Products: Rezurock (belumosudil) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, 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) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
- Specific Function
- anandamide 11,12 epoxidase activity
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- FDA Approved Drug Products: Rezurock (belumosudil) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- 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:12181437, PubMed:15470161, PubMed:15472229, PubMed:18004212, PubMed:18052087, PubMed:18674515, PubMed:19545173). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol and estrone (PubMed:15472229). Also catalyzes the glucuronidation of the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist caderastan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:20610558). Also metabolizes mycophenolate, an immunosuppressive agent (PubMed:15470161, PubMed:18004212)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A9
- Uniprot ID
- O60656
- Uniprot Name
- UDP-glucuronosyltransferase 1A9
- Molecular Weight
- 59940.495 Da
References
- FDA Approved Drug Products: Rezurock (belumosudil) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). 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:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
- Specific Function
- aromatase activity
- Gene Name
- CYP1A2
- Uniprot ID
- P05177
- Uniprot Name
- Cytochrome P450 1A2
- Molecular Weight
- 58406.915 Da
References
- FDA Approved Drug Products: Rezurock (belumosudil) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- 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: Rezurock (belumosudil) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- 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:12181437, PubMed:15472229, PubMed:18004206, PubMed:18004212, PubMed:18719240, PubMed:19830808, PubMed:23288867). Essential for the elimination and detoxification of drugs, xenobiotics and endogenous compounds (PubMed:12181437, PubMed:18004206, PubMed:18004212). Catalyzes the glucuronidation of endogenous estrogen hormones such as estradiol, estrone and estriol (PubMed:15472229, PubMed:18719240, PubMed:23288867). Involved in the glucuronidation of bilirubin, a degradation product occurring in the normal catabolic pathway that breaks down heme in vertebrates (PubMed:17187418, PubMed:18004206, PubMed:19830808, PubMed:24525562). Also catalyzes the glucuronidation the isoflavones genistein, daidzein, glycitein, formononetin, biochanin A and prunetin, which are phytoestrogens with anticancer and cardiovascular properties (PubMed:18052087, PubMed:19545173). Involved in the glucuronidation of the AGTR1 angiotensin receptor antagonist losartan, a drug which can inhibit the effect of angiotensin II (PubMed:18674515). Involved in the biotransformation of 7-ethyl-10-hydroxycamptothecin (SN-38), the pharmacologically active metabolite of the anticancer drug irinotecan (PubMed:12181437, PubMed:18004212, PubMed:20610558)
- Specific Function
- enzyme binding
- Gene Name
- UGT1A1
- Uniprot ID
- P22309
- Uniprot Name
- UDP-glucuronosyltransferase 1A1
- Molecular Weight
- 59590.91 Da
References
- FDA Approved Drug Products: Rezurock (belumosudil) tablets for oral use [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- FDA Approved Drug Products: Rezurock (belumosudil) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Functions as a transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
- Specific Function
- Not Available
- Gene Name
- ORM1
- Uniprot ID
- P02763
- Uniprot Name
- Alpha-1-acid glycoprotein 1
- Molecular Weight
- 23539.43 Da
References
- FDA Approved Drug Products: Rezurock (belumosudil) tablets for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitor
- 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: Rezurock (belumosudil) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Broad substrate specificity ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes a wide variety of physiological compounds, dietary toxins and xenobiotics from cells (PubMed:11306452, PubMed:12958161, PubMed:19506252, PubMed:20705604, PubMed:28554189, PubMed:30405239, PubMed:31003562). Involved in porphyrin homeostasis, mediating the export of protoporphyrin IX (PPIX) from both mitochondria to cytosol and cytosol to extracellular space, it also functions in the cellular export of heme (PubMed:20705604, PubMed:23189181). Also mediates the efflux of sphingosine-1-P from cells (PubMed:20110355). Acts as a urate exporter functioning in both renal and extrarenal urate excretion (PubMed:19506252, PubMed:20368174, PubMed:22132962, PubMed:31003562, PubMed:36749388). In kidney, it also functions as a physiological exporter of the uremic toxin indoxyl sulfate (By similarity). Also involved in the excretion of steroids like estrone 3-sulfate/E1S, 3beta-sulfooxy-androst-5-en-17-one/DHEAS, and other sulfate conjugates (PubMed:12682043, PubMed:28554189, PubMed:30405239). Mediates the secretion of the riboflavin and biotin vitamins into milk (By similarity). Extrudes pheophorbide a, a phototoxic porphyrin catabolite of chlorophyll, reducing its bioavailability (By similarity). Plays an important role in the exclusion of xenobiotics from the brain (Probable). It confers to cells a resistance to multiple drugs and other xenobiotics including mitoxantrone, pheophorbide, camptothecin, methotrexate, azidothymidine, and the anthracyclines daunorubicin and doxorubicin, through the control of their efflux (PubMed:11306452, PubMed:12477054, PubMed:15670731, PubMed:18056989, PubMed:31254042). In placenta, it limits the penetration of drugs from the maternal plasma into the fetus (By similarity). May play a role in early stem cell self-renewal by blocking differentiation (By similarity)
- Specific Function
- ABC-type xenobiotic transporter activity
- Gene Name
- ABCG2
- Uniprot ID
- Q9UNQ0
- Uniprot Name
- Broad substrate specificity ATP-binding cassette transporter ABCG2
- Molecular Weight
- 72313.47 Da
References
- FDA Approved Drug Products: Rezurock (belumosudil) tablets for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- 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: Rezurock (belumosudil) tablets for oral use [Link]
Drug created at July 19, 2021 06:02 / Updated at December 01, 2022 11:30