Fruquintinib

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
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 rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofMetastatic colorectal cancer (crc)••••••••••••••••••••••••• ••••••••• •••• ••••••••••••••••• ••••••••••• ••• ••••••••••• ••• ••••••••• •••• •••••••• •• ••••••••• •••••••• •••••••••• ••••••• •••• ••••••••••••••••
Treatment ofMetastatic colorectal cancer (crc)••••••••••••••••••••••••• ••••••••• •••• ••••••••••••••••• ••••••••••• ••• ••••••••••• •••••••••• ••••••• •••• ••••••••••••••••
Contraindications & Blackbox Warnings
Prevent Adverse Drug Events Today
Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events with our Clinical API
Learn more
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

TargetActionsOrganism
AVascular endothelial growth factor receptor 1
inhibitor
Humans
AVascular endothelial growth factor receptor 2
inhibitor
Humans
AVascular endothelial growth factor receptor 3
inhibitor
Humans
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 outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!
See the data
Improve decision support & research outcomes with our structured adverse effects data.
See a data sample
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
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
AbametapirThe serum concentration of Fruquintinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Fruquintinib can be increased when combined with Abatacept.
AbirateroneThe metabolism of Fruquintinib can be decreased when combined with Abiraterone.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Fruquintinib.
AcalabrutinibThe 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 regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FruzaqlaCapsule5 mg/1OralTakeda Pharmaceuticals America, Inc.2023-11-08Not applicableUS flag
FruzaqlaCapsule1 mg/1OralTakeda Pharmaceuticals America, Inc.2023-11-08Not applicableUS flag

Categories

Drug Categories
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
  1. 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]
  2. 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]
  3. Bergers G, Benjamin LE: Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003 Jun;3(6):401-10. doi: 10.1038/nrc1093. [Article]
  4. Kerbel RS: Tumor angiogenesis. N Engl J Med. 2008 May 8;358(19):2039-49. doi: 10.1056/NEJMra0706596. [Article]
  5. FDA Approved Drug Products: FRUZAQLA™ (fruquintinib) capsules, for oral use [Link]
  6. FDA approves fruquintinib in refractory metastatic colorectal cancer [Link]
PubChem Compound
44480399
PubChem Substance
347828047
ChemSpider
39625837
RxNav
2670179
ChEMBL
CHEMBL4303214
ZINC
ZINC000114898570
Wikipedia
Fruquintinib

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentColorectal Cancer / Her-21
4RecruitingTreatmentMetastatic Colorectal Cancer (CRC)1
3Active Not RecruitingTreatmentMetastatic Colon Cancer / Metastatic Colorectal Cancer (CRC)1
3Active Not RecruitingTreatmentStage IV Gastric Cancer1
3CompletedTreatmentColorectal Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral1 mg/1
CapsuleOral5 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US11046674No2015-09-072035-09-07US flag
US10519142No2015-09-072035-09-07US flag
US8212033No2008-05-092028-05-09US flag
US7829574No2008-05-092028-05-09US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0803 mg/mLALOGPS
logP3.12ALOGPS
logP2.64Chemaxon
logS-3.7ALOGPS
pKa (Strongest Acidic)14.99Chemaxon
pKa (Strongest Basic)2.57Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area95.71 Å2Chemaxon
Rotatable Bond Count5Chemaxon
Refractivity106.25 m3·mol-1Chemaxon
Polarizability40.64 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-0009000000-6baecadcf76545bf3526
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-03el-0309000000-b83383497e801c36ddd4
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-01pc-1009000000-25e22dbdd2aa55467a4d
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-03dm-1209000000-97522a0faa04bae2a525
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-05g3-0229000000-733f10d5eaf836852efa
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-1927000000-079ea5756e0152590870
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-190.9132
predicted
DeepCCS 1.0 (2019)
[M+H]+193.27121
predicted
DeepCCS 1.0 (2019)
[M+Na]+199.94865
predicted
DeepCCS 1.0 (2019)

Targets

Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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
  1. 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