Fruquintinib Chemical Properties

Boiling point:

600.5±55.0 °C(Predicted)

Density 

1.302±0.06 g/cm3(Predicted)

storage temp. 

Sealed in dry,Store in freezer, under -20°C

solubility 

Soluble in DMSO (up to 5 mg/ml).

pka

14.35±0.46(Predicted)

form 

solid

color 

White

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.

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)

InChIKey

BALLNEJQLSTPIO-UHFFFAOYSA-N

SMILES

O1C2=CC(OC3=C4C(=NC=N3)C=C(OC)C(OC)=C4)=CC=C2C(C(NC)=O)=C1C

Fruquintinib Usage And Synthesis

Description

Fruquintinib is a VEGFR inhibitor (IC₅₀s = 33, 35, and 0.5 nM for VEGFR1, -2, and -3, respectively). It also inhibits RET, FGFR1, and c-Kit (IC₅₀s = 128, 181, and 458 nM, respectively) in a panel of 253 kinases. Fruquintinib inhibits VEGF-A-induced proliferation of human umbilical vein endothelial cells (HUVECs) and VEGF-C-induced proliferation of human lymphatic endothelial cells (HLECs; IC₅₀s = 1.7 and 4.2 nM, respectively). It decreases tube formation by HUVECs by 74 and 94% when used at concentrations of 30 and 300 nM, respectively. Fruquintinib (0.5-20 mg/kg per day for 21 days) reduces tumor growth in BGC-823, HT-29, Caki-1, and NCI H460 mouse xenograft models.

Uses

Fruquintinib (HMPL-013) is a highly selective VEGFR-1/2/3 tyrosine kinase inhibitor. It was approved by the FDA on 8 November 2023 for the treatment of adult patients with metastatic colorectal cancer. and these patients had previously received fluoropyrimidine, oxaliplatin and irinotecan chemotherapy, anti-vascular endothelial growth factor therapy, and anti-epidermal growth factor receptor (EGFR) therapy. Fruquintinib has also been shown to improve cognitive deficits and pathological changes in a mouse model of cerebral amyloid angiopathy (CAA).

Uses

Fruquintinib is a multi-targeted tyrosine kinase inhibitor, a third-line regimen involved in the treatment of advanced non-small cell lung cancer in humans. Fruquintinib is a potent, highly selective and orally active inhibitor of VEGFR1, 2, 3 tyrosine kinases.

brand name

Fruzaqla

Mechanism of action

By blocking the vascular endothelial growth factor signalling pathway, Fruquintinib inhibits the formation of new blood vessels in tumours, thereby reducing blood supply and inhibiting tumour growth.

Side effects

The most common side effects of Fruquintinib|HMPL-013 include hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia.

Synthesis

Example 1 Synthesis of 6-((6,7-dimethoxyquinazolin-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide: 4-Chloro-6,7-dimethoxyquinazoline (1 eq.) was dissolved in 2 mL of acetonitrile, followed by addition of 6-hydroxy-N,2-dimethylbenzofuran-3-carboxamide (1 eq.) and potassium carbonate (1.5 eq.). The reaction mixture was refluxed under stirring conditions for 10 hours. After completion of the reaction, the solvent was removed by evaporation, the residue was washed with water, dried over anhydrous magnesium sulfate, filtered, concentrated and finally purified by column chromatography to afford the target compound 6-((6,7-dimethoxyquinazolin-4-yl)oxy)-N,2-dimethylbenzofuran-3-carboxamide in 85% yield. The product was characterized by 1H NMR (DMSO-d6, 400 MHz) and mass spectrometry (MS): 1H NMR δ 2.49 (s, 3H), 2.81 (d, J = 8.4 Hz, 3H), 3.97 (s, 3H), 3.98 (s, 3H), 7.24 (dd, J = 2.0, 8.4 Hz, 1H), 7.38 (s, 1H), 7.58 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.96 (m, 1H), 8.52 (s, 1H); MS (m/e): 394.1 (M + 1).

in vitro

fruquintinib was found to inhibit vegfr2 with an ic50 of 25 nmol/l. the kinase selectivity of fruquintinib was evaluated against a panel of 253 kinases. the results showed that fruquintinib inhibited vegfr family members with weak inhibition of ret, fgfr-1 and c-kit kinases [1].

in vivo

anti-tumor activity of fruquintinib was evaluated in a variety of tumor xenografts. the results from gastric cancer bgc-823 model seemed to indicate that the drug concentration needs to be at least maintained above ec85 for around 8 hours in order to achieve >80% tumor growth inhibition. bgc-823 was found to be most sensitive to fruquintinib [1].

IC 50

33 nmol/l, 35 nmol/l and 0.5 nmol/l for vegfr1, 2, 3

References

[1] QIAOLING SUN. Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy.[J]. Cancer Biology & Therapy, 2014, 15 12: 1635-1645. DOI:10.4161/15384047.2014.964087
[2] JIN LI. Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer: The FRESCO Randomized Clinical Trial.[J]. Jama-Journal of the American Medical Association, 2018, 319 24: 2486-2496. DOI:10.1001/jama.2018.7855
[3] SHUN LU. Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase II Study of Fruquintinib After Two Prior Chemotherapy Regimens in Chinese Patients With Advanced Nonsquamous Non‒Small-Cell Lung Cancer.[J]. Journal of Clinical Oncology, 2018: 1207-1217. DOI:10.1200/jco.2017.76.7145

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