Fruquintinib

Identification

Summary

Fruquintinib is a VEGF receptor inhibitor used to treat metastatic colorectal cancer

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

Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Fruquintinib (DB11679)

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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

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Associated Conditions

• Metastatic Colorectal Cancer (CRC)

Contraindications & Blackbox Warnings

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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	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 (C_max) is 300 ng/mL (28%) and the area under the concentration-time curve for the dosing interval (AUC_0-24h) is 5880 ng∙h/mL (29%) at the recommended dosage. The fruquintinib C_max and AUC_0-24h 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 AUC_0-24h accumulation of 4-fold.⁵

The fruquintinib median (min, max) time to C_max 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

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Apalutamide	The serum concentration of Fruquintinib can be decreased when it is combined with Apalutamide.
Bexarotene	The serum concentration of Fruquintinib can be decreased when it is combined with Bexarotene.
Bosentan	The serum concentration of Fruquintinib can be decreased when it is combined with Bosentan.
Carbamazepine	The serum concentration of Fruquintinib can be decreased when it is combined with Carbamazepine.
Dexamethasone	The serum concentration of Fruquintinib can be decreased when it is combined with Dexamethasone.
Dexamethasone acetate	The serum concentration of Fruquintinib can be decreased when it is combined with Dexamethasone acetate.
Echinacea	The serum concentration of Fruquintinib can be decreased when it is combined with Echinacea.
Efavirenz	The serum concentration of Fruquintinib can be decreased when it is combined with Efavirenz.
Enzalutamide	The serum concentration of Fruquintinib can be decreased when it is combined with Enzalutamide.
Etravirine	The serum concentration of Fruquintinib can be decreased when it is combined with Etravirine.

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Food Interactions

• Take with or without food. Take fruquintinib about the same time each day with or without food and swallow the capsule whole.

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 / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives

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Substituents

Alkyl aryl ether / Anisole / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Benzofuran / Carboxamide group / Carboxylic acid derivative / Diaryl ether / Furan / Furan-3-carboxylic acid or derivatives / Furoic acid or derivatives / Heteroaromatic compound / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide / Organoheterocyclic compound / Organonitrogen compound / Oxacycle / Phenol ether / Pyrimidine / Quinazoline / Secondary carboxylic acid amide

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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. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fruquintinib-refractory-metastatic-colorectal-cancer [Link]

External Links

PubChem Compound

44480399

PubChem Substance

347828047

ChemSpider

39625837

ChEMBL

CHEMBL4303214

ZINC

ZINC000114898570

Wikipedia

Fruquintinib

Clinical Trials

Clinical Trials

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
3	Completed	Treatment	Non-Small Cell Lung Cancer (NSCLC)	1
3	Enrolling by Invitation	Treatment	Advanced Malignant Neoplasm	1
3	Not Yet Recruiting	Treatment	Gastric Cancer	1
2	Active Not Recruiting	Treatment	Neoplasm of Stomach	1
2	Active Not Recruiting	Treatment	Patients With Advanced Metastatic Colorectal Cancer	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Not Available

Prices

Not Available

Patents

Not Available

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	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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insights and accelerate drug research.

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Details1. Vascular endothelial growth factor receptor 1

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]

Details2. Vascular endothelial growth factor receptor 2

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]

Details3. Vascular endothelial growth factor receptor 3

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]

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Drug created at October 20, 2016 20:39 / Updated at December 01, 2023 10:35