Fruquintinib

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Fruquintinib
File:Fruquintinib.svg
Clinical data
Trade namesFruzaqla
Other namesHMPL-013
AHFS/Drugs.comMonograph
MedlinePlusa623060
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classAntineoplastic
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein bindingPlasma protein binding of fruquintinib is approximately 95%.
MetabolismFruquintinib 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 metabolism. [9]
MetabolitesThe potency of M11 for inhibiting VEGFR-2 kinase activity is 10 times lower than that of fruquintinib (Takeda data on file); therefore, M11 is not considered an active metabolite.
Elimination half-life42hr
ExcretionA previous study reported that following administration of 5 mg of radiolabeled fruquintinib, approximately 60% of the dose was recovered in urine (0.50% unchanged) and 30% was recovered in feces (5.34% unchanged), with the remaining radioactivity excreted as metabolites.
Identifiers
  • 6-[(6,7-dimethoxyquinazolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number{{#property:P628}}
CompTox Dashboard (EPA)
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Chemical and physical data
FormulaC21H19N3O5
Molar mass393.399 g·mol−1
3D model (JSmol)
Solubility in waterThe aqueous

solubility of fruquintinib is pH-dependent, with a solubility of 0.9 μg/mL at pH 6.8 that increases under acidic conditions to 129.9 μg/mL at pH 1.

Fruquintinib is soluble in organic solvents such as DMSO and dimethyl formamide (DMF). The solubility of fruquintinib in these solvents is approximately

2 and 5 mg/ml, respectively. [10]
  • CNC(=O)C1=C(C)OC2=CC(OC3=NC=NC4=CC(OC)=C(OC)C=C34)=CC=C12
  • 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)
  • Key:BALLNEJQLSTPIO-UHFFFAOYSA-N

Fruquintinib, sold under the brand name Fruzaqla, is an anti-cancer medication used for the treatment of colorectal cancer.[6] Fruquintinib is a kinase inhibitor.[6] It is taken by mouth.[6]

The most common adverse reactions include hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia.[11]

Fruquintinib was approved for medical use in the United States in November 2023.[11][12]

Medical uses

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Fruquintinib is indicated for adults with metastatic colorectal cancer 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.[6][11][13][14]

Pharmacology

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The earlier generation small molecule VEGFR inhibitors, such as sunitinib,22 sorafenib,23 regorafenib24 and pazopanib25 suffer from poor kinome selectivity. In fact, many of them inhibit more than 10 kinases at similar potency. [15]

Fruquintinib is a highly potent and selective VEGFR 1, 2, 3 inhibitor

Fruquintinib was found to inhibit VEGFR2 (KDR) with an IC50 of 25 nmol/L in the Z-lyte assay. The kinase selectivity of fruquintinib was evaluated against a panel of 253 kinases using [32p-ATP] incorporation assay by Upstate Biotechnology Inc. (UBI) (Fig. 1B). The results showed that fruquintinib inhibited VEGFR family member (VEGFR1, 2, 3) with IC50s of 33 nmol/L, 35 nmol/L and 0.5 nmol/L, respectively with weak inhibition of RET, FGFR-1 and c-kit kinases. No significant inhibition was found against all other kinases at 1 μmol/L

History

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Efficacy was evaluated in FRESCO-2 (NCT04322539) and FRESCO (NCT02314819).[11] FRESCO-2 (NCT04322539), an international, multicenter, randomized, double-blind, placebo-controlled trial, evaluated 691 participants with metastatic colorectal cancer who had disease progression during or after prior fluoropyrimidine-, oxaliplatin-, irinotecan-based chemotherapy, an anti-VEGF biological therapy an anti-EGFR biological therapy if RAS wild type, and at least one of trifluridine/tipiracil or regorafenib.[11] FRESCO, a multicenter, placebo-controlled trial conducted in China, evaluated 416 participants with metastatic colorectal cancer who had disease progression during or after prior fluoropyrimidine-, oxaliplatin, and irinotecan-based chemotherapy.[11]

Society and culture

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In April 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Fruzaqla, intended for the treatment of people with previously treated metastatic colorectal cancer (mCRC).[7][16] The applicant for this medicinal product is Takeda Pharmaceuticals International AG Ireland Branch.[7] Fruzaqla was approved for medical use in the United States in June 2024.[8]

References

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  7. ^ a b c Lua error in Module:Citation/CS1/Configuration at line 2172: attempt to index field '?' (a nil value). Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
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  10. ^ https://cdn.caymanchem.com/cdn/insert/29425.pdf [bare URL PDF]
  11. ^ a b c d e f Lua error in Module:Citation/CS1/Configuration at line 2172: attempt to index field '?' (a nil value). Public Domain This article incorporates text from this source, which is in the public domain.
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  • Clinical trial number NCT04322539 for "A Study of Efficacy and Safety of Fruquintinib (HMPL-013) in Participants With Metastatic Colorectal Cancer (FRESCO-2)" at ClinicalTrials.gov
  • Clinical trial number NCT02314819 for "A Phase III Trial Evaluating Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer participants （FRESCO) (FRESCO)" at ClinicalTrials.gov

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