Administration of FGF19 - a physiological regulator of bile acid homeostasis - to diabetic and diet-induced-obese mice can suppress plasma glucose concentration and improve insulin sensitivity.  Repurposing FGF19 as a therapeutic agent for treating type 2 diabetes and cholestatic liver disease is therefore of significant interest.  However, the tumorigenic risk associated with prolonged FGF19 administration is a major hurdle in realizing its full clinical potential.  Here we show that non-mitogenic FGF19 variants that retain full beneficial glucose-lowering activity of wild-type FGF19 (FGF19WT) can be engineered by diminishing FGF19s ability to induce dimerization of its cognate FGF receptors (FGFR).  As proof-of-principle, we generated three such mutants, each with a partial defect in binding affinity to FGFR (FGF19FGFR), and its co-receptors klotho (FGF19KLB) or heparan sulfate (FGF19HBS).  Pharmacological assays in healthy and db/db mice confirmed that these variants incur a dramatic loss in mitogenic activity, yet are indistinguishable from FGF19WT in eliciting glycemic control.  Our approach provides a simple framework for the development of safer and efficacious FGF19 analogs. SOURCE: Jianlou Niu (niujianlou@wmu.edu.cn) -  Wenzhou Medical University

Pluto Bioinformatics

GSE148997: Alleviating FGF19s tumorigenic risk by suppressing its FGF Receptor dimerization ability