Identification
- Summary
Fruquintinib is a VEGF receptor inhibitor used to treat metastatic colorectal cancer.
- Brand Names
- Fruzaqla
- Generic Name
- Fruquintinib
- DrugBank Accession Number
- DB11679
- Background
Fruquintinib is a novel small-molecule anti-VEGFR that targets VEGFR-1,-2, and -3 to inhibit angiogenesis. Tumor angiogenesis is one of the most critical biological processes for increasing oxygen and nutrient supply to cancer cells, and the VEGF/VEGFR pathway is one of the most critical pathways for this phenomenon.3,4 Indeed, oncogenic activation, loss of tumor suppressor function, and hypoxia, usually facilitated by cancer cells, are known to upregulate VEGF.2
There are 2 major approaches to combatting tumor angiogenesis: neutralization of VEGF/VEGFR activity through monoclonal antibodies or blockage of VEGFR kinase activity through small-molecule inhibitors. The first approach can be exemplified by bevacizumab, a VEGF-A trap antibody. Although bevacizumab is successful in sustaining target inhibition, mandatory intravenous dosing, immunogenicity, and the potential to induce autoimmune diseases hinder its clinical application.2 For the small-molecule approach, most earlier generations of VEGFR inhibitors such as sunitinib, sorafenib, regorafenib, and pazopanib have poor selectivity, thus increasing the risk of off-target toxicity. Therefore, the advent of fruquintinib, a new generation of VEGFR inhibitors with a high kinome selectivity, demonstrated the feasibility of the small-molecule inhibitor approach.2
On November 8th, 2023, fruquintinib was approved by the FDA under the brand name Fruzaqla for the treatment of adult patients with metastatic colorectal cancer (mCRC) who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy. This approval is based on favorable results obtained from the FRESCO and FRESCO-2 trials, where an increase in overall survival rate was observed in both trials.6
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Fruquintinib (DB11679)
- Weight
- Average: 393.399
Monoisotopic: 393.132470724 - Chemical Formula
- C21H19N3O5
- Synonyms
- Fruquintinib
- External IDs
- HMPL-013
Pharmacology
- Indication
Fruquintinib is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR 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 Metastatic colorectal cancer (crc) •••••••••••• ••••• •••••••• ••••••••• •••• ••••••••••••••••• ••••••••••• ••• ••••••••••• ••• ••••••••• •••• •••••••• •• ••••••••• •••••••• •••••••••• ••••••• •••• ••••••••• ••••••• Treatment of Metastatic colorectal cancer (crc) •••••••••••• ••••• •••••••• ••••••••• •••• ••••••••••••••••• ••••••••••• ••• ••••••••••• •••••••••• ••••••• •••• ••••••••• ••••••• - 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
In vitro studies showed fruquintinib inhibited VEGF-mediated endothelial cell proliferation and tubular formation, while in vivo studies demonstrated fruquintinib-mediated tumor growth inhibition in a tumor xenograft mouse model of colon cancer. Inhibition of VEGF-induced VEGFR-2 phosphorylation was illustrated in both in vitro and in vivo studies.5
Fruquintinib exposure-response relationships and the time course of pharmacodynamic response are unknown. A mean increase in QTc interval >20 milliseconds (ms) was not observed at the approved recommended dosage.5
- Mechanism of action
Fruquintinib is a small-molecule kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 with IC50 values of 33, 35, and 0.5 nM, respectively
Target Actions Organism AVascular endothelial growth factor receptor 1 inhibitorHumans AVascular endothelial growth factor receptor 2 inhibitorHumans AVascular endothelial growth factor receptor 3 inhibitorHumans - Absorption
The fruquintinib steady-state geometric mean (% coefficient of variation [CV]) maximum concentration (Cmax) is 300 ng/mL (28%) and the area under the concentration-time curve for the dosing interval (AUC0-24h) is 5880 ng∙h/mL (29%) at the recommended dosage. The fruquintinib Cmax and AUC0-24h are dose-proportional across the dosage range of 1 to 6 mg (0.2 to 1.2 times the recommended dosage). Fruquintinib steady state is achieved after 14 days with a mean AUC0-24h accumulation of 4-fold.5
The fruquintinib median (min, max) time to Cmax is approximately 2 hours (0, 26 hours).5
No clinically significant differences in fruquintinib pharmacokinetics were observed following administration of a high-fat meal (800 to 1000 calories, 50% fat).5
- Volume of distribution
The mean (SD) apparent volume of distribution of fruquintinib is approximately 46 (13) L.5
- Protein binding
The plasma protein binding of fruquintinib is approximately 95%.5
- Metabolism
Fruquintinib is primarily eliminated by CYP450 and non-CYP450 (i.e., sulfation and glucuronidation) metabolism. CYP3A and to a lesser extent CYP2C8, CYP2C9, and CYP2C19 are the CYP450 enzymes involved in fruquintinib's metabolism.5
- Route of elimination
Following oral administration of a 5 mg radiolabeled fruquintinib dose, approximately 60% of the dose was recovered in urine (0.5% unchanged) and 30% of the dose was recovered in feces (5% unchanged).5
- Half-life
The fruquintinib's mean (SD) elimination half-life is approximately 42 (11) hours.5
- Clearance
The apparent clearance (SD) of fruquintinib is 14.8 (4.4) mL/min.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
Based on findings in animal studies and its mechanism of action, fruquintinib can cause fetal harm when administered to a pregnant woman. In an embryo-fetal developmental study in pregnant rats, oral administration of fruquintinib during the period of organogenesis resulted in teratogenicity and embryo lethality at exposures below the clinical exposure. There are no data on the use of fruquintinib in pregnant women. Advise pregnant women of the potential risk to a fetus.
Carcinogenicity studies have not been conducted with fruquintinib.
Fruquintinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenicin the in vitro Chinese hamster ovary chromosome aberration assay. Fruquintinib was not genotoxic in the in vivo rat micronucleus or alkaline comet assays.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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 Fruquintinib can be increased when it is combined with Abametapir. Abatacept The metabolism of Fruquintinib can be increased when combined with Abatacept. Abiraterone The metabolism of Fruquintinib can be decreased when combined with Abiraterone. Abrocitinib The metabolism of Abrocitinib can be decreased when combined with Fruquintinib. Acalabrutinib The metabolism of Fruquintinib can be decreased when combined with Acalabrutinib. - Food Interactions
- Take with or without food. Take fruquintinib about the same time each day with or without food and swallow the capsule whole.
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.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Fruzaqla Capsule 1 mg/1 Oral Takeda Pharmaceuticals America, Inc. 2023-11-08 Not applicable US 
Fruzaqla Capsule 5 mg/1 Oral Takeda Pharmaceuticals America, Inc. 2023-11-08 Not applicable US
Categories
- Drug Categories
- Cytochrome P-450 CYP2C19 Substrates
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 CYP3A7 Substrates
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
- Kingdom
- Organic compounds
- Super Class
- Organic oxygen compounds
- Class
- Organooxygen compounds
- Sub Class
- Ethers
- Direct Parent
- Diarylethers
- Alternative Parents
- Quinazolines / Benzofurans / Furan-3-carboxylic acid and derivatives / Anisoles / Alkyl aryl ethers / Pyrimidines and pyrimidine derivatives / Heteroaromatic compounds / Secondary carboxylic acid amides / Oxacyclic compounds / Azacyclic compounds show 3 more
- Substituents
- Alkyl aryl ether / Anisole / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Benzofuran / Carboxamide group / Carboxylic acid derivative / Diaryl ether / Furan show 13 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 49DXG3M5ZW
- CAS number
- 1194506-26-7
- InChI Key
- BALLNEJQLSTPIO-UHFFFAOYSA-N
- InChI
- InChI=1S/C21H19N3O5/c1-11-19(20(25)22-2)13-6-5-12(7-16(13)28-11)29-21-14-8-17(26-3)18(27-4)9-15(14)23-10-24-21/h5-10H,1-4H3,(H,22,25)
- IUPAC Name
- 6-[(6,7-dimethoxyquinazolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide
- SMILES
- CNC(=O)C1=C(C)OC2=CC(OC3=NC=NC4=CC(OC)=C(OC)C=C34)=CC=C12
References
- General References
- Zhang Y, Zou JY, Wang Z, Wang Y: Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer. Cancer Manag Res. 2019 Aug 16;11:7787-7803. doi: 10.2147/CMAR.S215533. eCollection 2019. [Article]
- Sun Q, Zhou J, Zhang Z, Guo M, Liang J, Zhou F, Long J, Zhang W, Yin F, Cai H, Yang H, Zhang W, Gu Y, Ni L, Sai Y, Cui Y, Zhang M, Hong M, Sun J, Yang Z, Qing W, Su W, Ren Y: Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy. Cancer Biol Ther. 2014;15(12):1635-45. doi: 10.4161/15384047.2014.964087. [Article]
- Bergers G, Benjamin LE: Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003 Jun;3(6):401-10. doi: 10.1038/nrc1093. [Article]
- Kerbel RS: Tumor angiogenesis. N Engl J Med. 2008 May 8;358(19):2039-49. doi: 10.1056/NEJMra0706596. [Article]
- FDA Approved Drug Products: FRUZAQLA™ (fruquintinib) capsules, for oral use [Link]
- FDA approves fruquintinib in refractory metastatic colorectal cancer [Link]
- External Links
- PubChem Compound
- 44480399
- PubChem Substance
- 347828047
- ChemSpider
- 39625837
- 2670179
- ChEMBL
- CHEMBL4303214
- ZINC
- ZINC000114898570
- Wikipedia
- Fruquintinib
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Active Not Recruiting Treatment Colorectal Cancer / Her-2 1 4 Recruiting Treatment Metastatic Colorectal Cancer (CRC) 1 3 Active Not Recruiting Treatment Metastatic Colon Cancer / Metastatic Colorectal Cancer (CRC) 1 3 Active Not Recruiting Treatment Stage IV Gastric Cancer 1 3 Completed Treatment Colorectal Cancer 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 1 mg/1 Capsule Oral 5 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US11046674 No 2015-09-07 2035-09-07 US US10519142 No 2015-09-07 2035-09-07 US US8212033 No 2008-05-09 2028-05-09 US US7829574 No 2008-05-09 2028-05-09 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0803 mg/mL ALOGPS logP 3.12 ALOGPS logP 2.64 Chemaxon logS -3.7 ALOGPS pKa (Strongest Acidic) 14.99 Chemaxon pKa (Strongest Basic) 2.57 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 95.71 Å2 Chemaxon Rotatable Bond Count 5 Chemaxon Refractivity 106.25 m3·mol-1 Chemaxon Polarizability 40.64 Å3 Chemaxon Number of Rings 4 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 splash10-0006-0009000000-6baecadcf76545bf3526 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-03el-0309000000-b83383497e801c36ddd4 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-01pc-1009000000-25e22dbdd2aa55467a4d Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-03dm-1209000000-97522a0faa04bae2a525 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-05g3-0229000000-733f10d5eaf836852efa Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0002-1927000000-079ea5756e0152590870 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]- 190.9132 predictedDeepCCS 1.0 (2019) [M+H]+ 193.27121 predictedDeepCCS 1.0 (2019) [M+Na]+ 199.94865 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Vegf-b-activated receptor activity
- Specific Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFB and PGF, and plays an essential role in the development of embryonic vasculature, the regulation of angiogenesis, cell ...
- Gene Name
- FLT1
- Uniprot ID
- P17948
- Uniprot Name
- Vascular endothelial growth factor receptor 1
- Molecular Weight
- 150767.185 Da
References
- FDA Approved Drug Products: FRUZAQLA™ (fruquintinib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Vascular endothelial growth factor-activated receptor activity
- Specific Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and ...
- Gene Name
- KDR
- Uniprot ID
- P35968
- Uniprot Name
- Vascular endothelial growth factor receptor 2
- Molecular Weight
- 151525.555 Da
References
- FDA Approved Drug Products: FRUZAQLA™ (fruquintinib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Vascular endothelial growth factor-activated receptor activity
- Specific Function
- Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFC and VEGFD, and plays an essential role in adult lymphangiogenesis and in the development of the vascular network and the cardi...
- Gene Name
- FLT4
- Uniprot ID
- P35916
- Uniprot Name
- Vascular endothelial growth factor receptor 3
- Molecular Weight
- 152755.94 Da
References
- FDA Approved Drug Products: FRUZAQLA™ (fruquintinib) capsules, for oral use [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid 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 oxidizes a variety of structurally un...
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- FDA Approved Drug Products: FRUZAQLA™ (fruquintinib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Steroid 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 oxidizes a variety of structurally un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- FDA Approved Drug Products: FRUZAQLA™ (fruquintinib) capsules, 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
- FDA Approved Drug Products: FRUZAQLA™ (fruquintinib) capsules, 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
- FDA Approved Drug Products: FRUZAQLA™ (fruquintinib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Oxygen binding
- 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 oxidizes a variety of structurally un...
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- FDA Approved Drug Products: FRUZAQLA™ (fruquintinib) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Oxygen binding
- 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 oxidizes a variety of structurally un...
- Gene Name
- CYP3A7
- Uniprot ID
- P24462
- Uniprot Name
- Cytochrome P450 3A7
- Molecular Weight
- 57525.03 Da
References
- FDA Approved Drug Products: FRUZAQLA™ (fruquintinib) capsules, for oral use [Link]
Drug created at October 20, 2016 20:39 / Updated at January 09, 2024 06:15