Introduction: fibroblast growth factor receptors (FGFRs) are a family of tyrosine-kinase receptors whose signaling cascade regulates cellular proliferation, differentiation, and survival. Deregulation of the FGFR pathway is recognized as a driving factor in tumor development. On this basis, FGFR is an attractive target for anti-cancer small-molecule therapeutic agents.Areas covered: This review summarizes patent and literature publications spanning from 2015 to 2019 pertaining to small-molecule FGFR kinase inhibitors.Expert opinion: The first generation of non-covalent FGFR inhibitors is characterized by a broad spectrum of activity and a relatively high toxicity profile. The second generation of FGFR inhibitors shows higher selectivity and a more favorable toxicity profile, but the clinical use appears restricted only to small subsets of cancers strongly dependent on FGFR signaling. Nevertheless, erdafitinib has been approved for the treatment of metastatic urothelial carcinoma, becoming the first marketed selective FGFR inhibitor. The insurgence of mutant kinases, resistant to available therapies, has led to the development of irreversible FGFR inhibitors. The adoption of safer and more selective covalent inhibitors might supersede reversible inhibitors in specific therapeutic areas. Alternative strategies, such as FGF trapping by protein or small-molecule therapeutics, deserve attention and further investigations to unravel their potential.
Keywords: FGFR inhibitors; Fibroblast growth factor receptor; cancer; covalent inhibitors.