Fruquintinib

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]

Fruquintinib

Clinical data
Trade names	Fruzaqla
Other names	HMPL-013
AHFS/Drugs.com	Monograph
MedlinePlus	a623060
License data	US DailyMed: Fruquintinib
Pregnancy category	AU: D[1]
Routes of administration	By mouth
Drug class	Antineoplastic
ATC code	L01EK04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[2][3] CA: ℞-only[4][5] US: ℞-only[6] EU: Rx-only[7][8]
Pharmacokinetic data
Protein binding	Plasma protein binding of fruquintinib is approximately 95%.
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 metabolism. [9]
Metabolites	The 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-life	42hr
Excretion	A 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
IUPAC name 6-[(6,7-dimethoxyquinazolin-4-yl)oxy]-N,2-dimethyl-1-benzofuran-3-carboxamide
CAS Number	1194506-26-7
PubChem CID	44480399
IUPHAR/BPS	9428
DrugBank	DB11679
ChemSpider	39625837
UNII	49DXG3M5ZW
KEGG	D11977
ChEBI	CHEBI:229221
ChEMBL	ChEMBL4303214
Chemical and physical data
Formula	C21H19N3O5
Molar mass	393.399 g·mol−1
3D model (JSmol)	Interactive image
Solubility in water	The 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]
SMILES CNC(=O)C1=C(C)OC2=CC(OC3=NC=NC4=CC(OC)=C(OC)C=C34)=CC=C12
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) Key:BALLNEJQLSTPIO-UHFFFAOYSA-N

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

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

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

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

Legal status

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]