Chemistry:Fruquintinib
Fruquintinib, sold under the brand name Fruzaqla, is an anti-cancer medication used for the treatment of colorectal cancer.[1] Fruquintinib is a kinase inhibitor.[1] It is taken by mouth.[1]
The most common adverse reactions include hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, abdominal pain, diarrhea, and asthenia.[2]
Fruquintinib was approved for medical use in the United States in November 2023.[2][3]
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.[1][2][4][5]
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. [6]
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).[2] 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.[2] 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.[2]
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][8] 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.[9]
Synthesis
The last step in the synthesis of is disclosed.[10] In addition, a recent article outlining the synthesis of the precursor was also disclosed.[11]
An SNAr reaction between 4-Chloro-6,7-dimethoxyquinazoline [13790-39-1] (1) and 6-hydroxy-N,2-dimethylbenzofuran-3-carboxamide [638217-08-0] (2) afforded fruquintinib in 85% yield.
N.B. It is interesting to take stock that precursor 1 finds dual use in the synthesis of Buquineran, Hoquizil & Piquizil.
References
- ↑ 1.0 1.1 1.2 1.3 Cite error: Invalid
<ref>tag; no text was provided for refs namedFruzaqla FDA label - ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "FDA approves fruquintinib in refractory metastatic colorectal cancer". 8 November 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fruquintinib-refractory-metastatic-colorectal-cancer.
This article incorporates text from this source, which is in the public domain.
- ↑ "Takeda Receives U.S. FDA Approval of Fruzaqla (fruquintinib) for Previously Treated Metastatic Colorectal Cancer" (Press release). Takeda. 8 November 2023. Archived from the original on 8 November 2023. Retrieved 10 November 2023 – via Business Wire.
- ↑ "Efficacy and safety of regorafenib and fruquintinib as third-line treatment for colorectal cancer: a narrative review". Translational Cancer Research 11 (1): 276–287. January 2022. doi:10.21037/tcr-20-3539. PMID 35261903.
- ↑ "Evaluation of Fruquintinib in the Continuum of Care of Patients with Colorectal Cancer". International Journal of Molecular Sciences 24 (6): 5840. March 2023. doi:10.3390/ijms24065840. PMID 36982913.
- ↑ "Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy". Cancer Management and Research 11: 7787–7803. 2019. doi:10.2147/CMAR.S215533. PMID 31496821.
- ↑ 7.0 7.1 "Fruzaqla EPAR". 25 April 2024. https://www.ema.europa.eu/en/medicines/human/EPAR/fruzaqla. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ↑ "Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 22-25 April 2024". European Medicines Agency (Press release). 26 April 2024. Retrieved 13 June 2024.
- ↑ "Fruzaqla PI". 25 June 2024. https://ec.europa.eu/health/documents/community-register/html/h1827.htm.
- ↑ "Synthetic Approaches to New Drugs Approved during 2018". Journal of Medicinal Chemistry 63 (19): 10652–10704. 8 October 2020. doi:10.1021/acs.jmedchem.0c00345. https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00345.
- ↑ "Development of Two Synthetic Routes to a Benzofuran Intermediate for Fruquintinib". The Journal of Organic Chemistry 90 (48): 17015–17023. 5 December 2025. doi:10.1021/acs.joc.5c02114. https://pubs.acs.org/doi/10.1021/acs.joc.5c02114.
External links
- 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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