Current strategies for inhibiting FGFR activities in clinical applications: opportunities, challenges and toxicological considerations

•Dysregulation of fibroblast growth factor receptor (FGFR) signaling in many diseases prompts development of inhibitors.•Inhibitors are derived from rational design and existing kinase inhibitors.•Monoclonal antibody/ligand traps are alternative strategies in early development.•Role of FGFR in normal physiology and homeostasis could impose toxicity risks.•Achieving target selectivity remains a challenge owing to the high degree of homology.

Aberrations in fibroblast growth factor receptor (FGFR) signaling are instrumental to the pathophysiology of several malignancies and disorders. Hence, FGFR inhibitors are explored in therapeutics with early candidates developed as competitors for the ATP-binding pocket in the kinase domain. More recent programs yielded compounds of diverse scaffolds with alternative binding modes. Concurrently, monoclonal antibodies and peptide-based agents provide independent options for clinical development. Notwithstanding this rapid progress, we contemplate the toxicological impact of FGFR inhibition based on the defined role of FGFR family members in physiology and homeostasis. The high homology among FGFR1–4 and also with other kinase subfamilies creates an additional challenge in developing selective inhibitors. It orchestrates an ongoing conundrum of moderating a balance between synergism through multitargeting kinase inhibition and minimizing off-target toxicities.