FGF-based drug discovery: advances and challenges

Abstract

The fibroblast growth factor (FGF) family comprises 15 paracrine-acting and 3 endocrine-acting polypeptides, which govern a multitude of processes in human development, metabolism and tissue homeostasis. Therapeutic endocrine FGFs have recently advanced in clinical trials, with FGF19 and FGF21-based therapies on the cusp of approval for the treatment of primary sclerosing cholangitis and metabolic syndrome-associated steatohepatitis, respectively. By contrast, while paracrine FGFs were once thought to be promising drug candidates for wound healing, burns, tissue repair and ischaemic ailments based on their potent mitogenic and angiogenic properties, repeated failures in clinical trials have led to the widespread perception that the development of paracrine FGF-based drugs is not feasible. However, the observation that paracrine FGFs can exert FGF hormone-like metabolic activities has restored interest in these FGFs. The recent structural elucidation of the FGF cell surface signalling machinery and the formulation of a new threshold model for FGF signalling specificity have paved the way for therapeutically harnessing paracrine FGFs for the treatment of a range of metabolic diseases. The fibroblast growth factor (FGF) family play critical regulatory roles in development, metabolism and tissue homeostasis and their therapeutic applications are being widely explored. This Review highlights recent advances in understanding of FGF signalling, discusses the current status of endocrine FGF-based drug development and assesses the emerging potential of harnessing paracrine FGFs in the treatment of metabolic diseases.