TABLE 2.
Therapeutic inhibition of FGF signaling pathways
| Mechanism, molecular target | Clinical, animal, or cellular target | Alternative or trade name | FDA approved/clinical trial | References | |
|---|---|---|---|---|---|
| A. Paracrine FGF signaling | |||||
| Small molecule inhibitors | |||||
| FGFR inhibitor | FGFR2, FGFR3 | Metastatic urothelial carcinoma | Erafitibnib | FDA approved | Hanna, 2019 |
| FGFR inhibitor | FGFR2, FGFR3 | Cholangiocarcinoma | Pemiganib, Infigratinib | FDA approved | Hoy, 2020; Kang, 2021; Rizzo et al., 2021 |
| FGFR inhibitor | FGFR2, FGFR3 | Achondroplasia (mouse), urothelial, hepatocellular, squamous cell lung cancer (human) | ASP5878 | Clinical trial | Futami et al., 2017; Kikuchi et al., 2017; Ozaki et al., 2020; Yamamoto et al., 2020 |
| FGFR inhibitor | FGFR2, FGFR3 | Pulmonary fibrosis; gastrointestinal stromal tumor; hepatocellular carcinoma; urothelial carcinoma; tumor-induced osteomalacia; Achondroplasia(mouse) | Infigratinib (BGJ398) | Komla-Ebri et al., 2016; Morizumi et al., 2020; Botrus et al., 2021; Florenzano et al., 2021; Hartley et al., 2020; Kelly et al., 2019; Pal et al., 2018; Prawira et al., 2021 | |
| FGFR inhibitor | FGFRs 1–4 | Urothelial, hepatocellular, squamous cell lung carcinoma | ASP5878 | Clinical trial | Yamamoto et al., 2020 |
| FGFR inhibitor | FGFRs 1–3 | Intrahepatic carcinoma | Derazantinib (ARQ087) | Clinical trial | Papadopoulos et al., 2017; Mazzaferro et al., 2019 |
| FGFR inhibitor (covalent) | FGFRs 1–4 | TAS-120 | Clinical trial | Kalyukina et al., 2019 | |
| FGFR inhibitor (covalent) | FGFRs 1–4 | Cancer cells, xenograft | PRN1371 | Clinical trial | Venetsanakos et al., 2017; Brameld et al., 2017 |
| FGFR inhibitor (covalent) | FGFRs 1–4 | Cholangiocarcinoma | Futibatinib | Clinical trial | Meric-Bernstam et al., 2021 |
| FGFR inhibitor (covalent) | FGFR4 selective | Hepatocellular carcinoma | H3B-6527 | Clinical trial | Joshi et al., 2017 |
| FGFR inhibitor (covalent) | FGFR4 selective | Hepatocellular carcinoma | Fisogatinib (BLU-554) | Clinical trial | Hatlen et al., 2019; Kim, Joe, Choi, et al., 2019 |
| FGFR inhibitor (covalent, reversible) | FGFR4 selective | Hepatocellular carcinoma | Roblitinib | Clinical trial | Fairhurst et al., 2020 |
| THBS1 or PTX3 based compounds | FGF2 | Antiangiogenic drugs (see NSC12 below) | Foglieni et al., 2016; Pagano et al., 2012; Presta et al., 2018; Ronca, Giacomini, Di Salle, et al., 2015; Ronca et al., 2017 | ||
| NSC12 (steroid derivative) | Pan-FGF | Extracellular pan-FGF trap derived from PTX3 structure | NSC12 | Castelli et al., 2016, 2021; Ronca, Giacomini, Di Salle, et al., 2015 | |
| MEK inhibitor and FGFR inhibitor | MEK and FGFR1 | Synergistical inhibition of cell proliferation in KRAS-mutant lung cancer | Trametinib and Ponatinib | Manchado et al., 2016 | |
| Peptide inhibitors | |||||
| FGF8b (13 amino acid peptide) | FGF8b–FGFR | Inhibition of prostate cancer cell line and HUVEC proliferation | 8b-13 | Li et al., 2013; Lin et al., 2017 | |
| 12 amino acid peptide | FGF2–FGFR1 | Attenuation of cartilage loss in osteoarthritis; attenuation of tumor growth and angiogenesis in xenograft model (mouse) | R1-P2, R1-P1 | Tan, Chen, et al., 2018; Tan, Wang, et al., 2018 | |
| Cyclic 10 amino acid peptide | FGF1–FGFR1 | Inhibition of FGF1 induced proliferation of BaF3 cells that express FGFR1c | F8 | Lipok et al., 2019; Ornitz et al., 1996 | |
| 12 amino acid peptide | FGFR3 | Rescues of viability of mice with Thanatophoric dysplasia type II mutation; inhibition of 9-cisRAinduced tracheal lymphangiogenesis (mouse) | P3 | Jin et al., 2012; Perrault et al., 2019 | |
| C-type natriuretic peptide (CNP) | NPR2 | Achondroplasia; Inhibition of FGFR3 induced ERK phosphorylation in growth plate chondrocytes | TransCon CNP; Vosoritide | Clinical trial | Breinholt et al., 2019; Savarirayan et al., 2020 |
| Protein or antibody inhibitors | |||||
| Soluble Fc-FGFR1c decoy receptor | FGF ligands | Decrease of tumor-associated angiogenesis in vivo; mesothelioma; non-small cell lung cancer | GSK3052230, FP-1039 | Clinical trial | Harding et al., 2013; Blackwell et al., 2016; Morgensztern et al., 2019; van Brummelen et al., 2020 |
| Anti-FGFR2b antibody | FGFR2b | Inhibition of advanced gastroesophageal cancer | Bemarituzumab | Clinical trial | Catenacci et al., 2019, 2020 |
| Anti-FGFR2-auristatin | FGFR2/microtubuledisrupting agent | Adverse effects in clinical trials | Aprutumab ixadotin | Clinical trial | S. B. Kim, Meric-Bernstam, Kalyan, et al., 2019 |
| Anti-FGFR3 antibody | FGFR3 | Inhibition of lung adenocarcinoma (mouse) | D11 | Yin et al., 2016 | |
| Soluble FGFR3 decoy receptor | FGF ligands | Increase of skeletal growth and reduction of visceral obesity in Achondroplasia (mouse) | Recifercept | Garcia et al., 2013; Goncalves et al., 2020; Saint-Laurent et al., 2018; Unger et al., 2017 | |
| Oligonucleotide aptamer inhibitors | |||||
| RNA aptamer to FGF2 | FGF2 | Improvement of arthritis, osteoporosis, and Achondroplasia, inhibition of neoangiogenesis in models of agerelated macular degeneration (mouse, rat); strong analgesic effect for bone cancer pain (mouse) | RBM-007 | Clinical trial | Jin et al., 2016; Hamamoto et al., 2018; Matsuda et al., 2019; Kimura et al., 2021; Nakamura, 2018, 2021 |
| RNA aptamer to FGF5 | FGF5 | Inhibition of FGF5-induced cell proliferation | F5f1–56 | Amano et al., 2021 | |
| DNA aptamer to FGFR1 | FGFR1 | Killing of FGFR-1 expressing human osteosarcoma cells | A11-G18T | Jurek et al., 2017 | |
| B. Endocrine FGF signaling | |||||
| Protein or antibody inhibitors | |||||
| Anti-FGF15/19 N-terminus monoclonal antibody | FGF15/19 | Inhibition hepatocellular carcinoma growth without bile-acid related side effects (mouse, monkey) | H. Liu, Zheng, et al., 2020 | ||
| FGF23 C-tail-Fc fusion | FGFR/αKlotho | Increase of serum phosphate in X-linked | FGF23 c-tail Fc | Johnson et al., 2017 protein | hypophosphatemia (mouse) |
| Anti-FGF23 monoclonal antibody | FGF23 | Treatment of chronic kidney disease; Xlinked hypophosphatemia | Burosumab (KRN23) | FDA approved | Carpenter et al., 2014, 2018; Fukumoto, 2014, 2021; X. Zhang, Ibrahimi, et al., 2006; Kutilek, 2017; Insogna et al., 2018; Lamb, 2018; Imel et al., 2019; Imel, 2021; Michigami, 2019; Dahir et al., 2020; Schindeler et al., 2020; Balani & Perwad, 2020; Schindeler et al., 2020; Gladding et al., 2021; Verbueken & Moe, 2021; Jan de Beur et al., 2021 |
| Anti-FGFR4 antibody | FGFR4 | Inhibition of FGF23-induced left ventricular hypertrophy (rat) | Grabner et al., 2015, 2017 | ||
| Peptide inhibitor | |||||
| FGF23 C-terminal 72 amino acid peptide | FGFR1/αKlotho | Prevention of FGF23-mediated anemia and iron deficiency (hypoferremia) in chronic kidney disease (mouse) | Agoro et al., 2018, 2021 |