Description

Erdafitinib, also known as JNJ-42756493, is a first-in-class pan-fibroblast growth factor receptor (FGFR) kinase inhibitor discovered by Astex Pharmaceuticals and Janssen. The chemical name of erdafitinib is N-(3,5-Dimethoxy-phenyl)-N'-isopropyl-N-[3-(1-methyl-1 H-pyrazole-4-yl)-quinoxalin-6-yl]-ethane-1,2-diamine[1].

Uses

The drug was approved by the USFDA for the treatment of metastatic urothelial carcinoma with specific FGFR2 and FGFR3 genetic mutations. Based on the results of the phase 2 BLC2001 trial (NCT02365597), in which erdafitinib showed an overall response rate of 40% in metastatic urothelial cancer (U) with FGFR3 mut/fus, it is the first approved targeted therapy in metastatic UC. Urothelial cancer, particularly of the bladder, is the sixth most common cancer, representing 4.5% of all new cancer cases, with an estimated 81,000 new cases and 17,980 deaths in 2020. The drug is also being investigated as a treatment for other cancers, including cholangiocarcinoma, liver cancer, non-small cell lung cancer, prostate cancer, lymphoma, and oesophageal cancer[2].

Biological activity

FGFR genetic mutations play a significant role in the pathogenesis of certain cancers, including urothelial cancer. Erdafitinib binds to and inhibits the enzymatic activity of FGFR1?4, inhibiting phosphorylation and cell signaling. In addition, erdafitinib also binds to Fmsrelated tyrosine kinase 4 (FLT4), the tyrosine?protein kinase c-KIT, and vascular endothelial growth factor receptor 2 (VEGFR-2).

Synthesis method

A gram-scale synthesis of erdafitinib has been described that starts with chlorination of 6-bromoquinoxaline [3]. Suzuki coupling of chloride 1 and pyrazole 2 provided bromide 3, which underwent Buchwald?Hartwig coupling with aniline 4. Alkylation of the secondary amine with bromide 6 followed by removal of the silyl ether, mesylation, and recrystallization with DIPE-provided compound 8. Displacement of the mesylate with isopropylamine and subsequent recrystallization from diethyl ether and acetonitrile furnished erdafitinib as the free base in 83% yield.

References

[1] L. Marandino. “Erdafitinib for the treatment of urothelial cancer.” Expert Review of Anticancer Therapy 19 1 (2019): 835–846.

[2] Markham, Anthony. “Erdafitinib: First Global Approval.” Drugs 79 9 (2019): 1017–1021.

[3] Andrew C. Flick. “Synthetic Approaches to the New Drugs Approved during 2019.” Journal of Medicinal Chemistry 64 7 (2021): 3604–3657.