Targeting FGFRs for Tumor Therapy: Current Status and Novel Strategies

Abstract

The FGF receptors (FGFRs) belong to a family of receptor tyrosine kinases. Abundant evidence shows that FGFRs are closely related to tumor cell invasion and angiogenesis. Hence, targeted modulation of FGFRs has become an effective strategy for cancer treatment. Recently, the development of small-molecule inhibitors targeting FGFRs has been extensively studied, and three inhibitors have been approved for marketing. Based on the clinical problems with the current inhibitors, there is a need to develop novel inhibitors and technologies to address the pitfalls. This review summarizes recent advances in small-molecule inhibitors targeting FGFRs, focusing on structure–activity relationships. Moreover, recent progress of novel technologies are summarized to provide a reference for promoting the application of drugs targeting FGFRs in tumor therapy.

Identification of Piperazinyl–Difluoro-indene Derivatives Containing Pyridyl Groups as Potent FGFR Inhibitors against FGFR Mutant Tumor: Design, Synthesis, and Biological Evaluation

“…Next, the influence of substitutes at the meta-position of nitrogen of the 3-pyridyl moiety on inhibitory activity was explored. Replacement of OMe by 2-methoxyethoxy (11) and N,N-dimethylamine (12) groups did not improve the inhibitory effects on MFE-296 cells, although the antiproliferative effects on H716 and KATO III cells were maintained. However, the substitution of an azetidyl (13) group, which is small in size, led to potent inhibition of MFE-296 cell proliferation.…”

“…8,9 To date, four FGFR inhibitors have been developed to treat solid tumors harboring FGFR alterations. 10,11 Erdafitinib (1), 12−14 pemigatinib (2), 15−17 infigratinib (3), 18,19 and futibatinib (4) 20,21 have been approved by the US Food and Drug Administration for the treatment of urothelial carcinoma harboring FGFR3 point mutations or fusion genes and cholangiocarcinoma harboring FGFR2 fusion genes or other rearrangements (Figure 1). Given that FGFRs are valuable targets for the development of new anticancer drugs, especially for refractory malignant tumors such as gastric carcinoma and endometrial adenocarcinoma, there still exists unmet medical needs for the development of inhibitors against FGFRs.…”

“…Fibroblast growth factor receptors (FGFRs) belong to the receptor tyrosine kinase family, and they include four highly conserved transmembrane receptors (FGFR1, FGFR2, FGFR3, and FGFR4) and a membrane-associated receptor lacking the intracellular domain (FGFRL1). , When different fibroblast growth factors (FGFs) bind to FGFRs, the FGFRs form dimers, leading to the intracellular phosphorylation of receptor kinase domains, thereby activating downstream signaling pathways, such as RAS-RaF-MEK-ERK, PLCγ-PKC, JAK-STAT, and PI3K-AKT signaling. − The FGF/FGFR signaling pathway plays crucial roles in cell proliferation and angiogenesis, embryonic and fetal development, tissue development, immune surveillance, and metabolism. However, abnormal activation of this signaling pathway, as induced by amplification, point mutations, translocation, and gene fusion, can lead to carcinogenesis. , FGFR alterations have been observed in several solid tumors, such as breast cancer, lung cancer, gastric cancer, urothelial carcinoma, liver cancer, bladder cancer, bile duct cancer, and endometrial adenocarcinoma. , To date, four FGFR inhibitors have been developed to treat solid tumors harboring FGFR alterations. , Erdafitinib ( 1 ), − pemigatinib ( 2 ), − infigratinib ( 3 ), , and futibatinib ( 4 ) , have been approved by the US Food and Drug Administration for the treatment of urothelial carcinoma harboring FGFR3 point mutations or fusion genes and cholangiocarcinoma harboring FGFR2 fusion genes or other rearrangements (Figure ). Given that FGFRs are valuable targets for the development of new anticancer drugs, especially for refractory malignant tumors such as gastric carcinoma and endometrial adenocarcinoma, there still exists unmet medical needs for the development of inhibitors against FGFRs.…”

“…1 H NMR (400 MHz, chloroform-d): δ 8.64 (s, 1H), 8.60 (s, 1H), 8.41 (d, J = 6.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.88−7.83 (m, 2H), 7.78 (dd, J = 8.0, 2.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 6.0 Hz, 1H), 4.49 (q, J = 6.4 Hz, 1H), 3.96 (s, 3H), 2.66−2.46 (m, 13H), and 2.29 (s, 3H). 13 (11). In a similar manner to 6, compound 11 was prepared from 47a and 48d (59 mg, a pale yellow solid, 42.1%).…”