The human fibroblast growth factor family consists of 22 factors and five 
transmembrane receptors. Of the 22 factors, eighteen are secreted while four of 
them function exclusively within the cell. Four of the fibroblast growth factor 
receptors (FGFRs) possess intracellular protein-tyrosine kinase activity while 
the fifth (FGFRL1) has a short 105-residue intracellular non-enzymatic 
component. The FGFR protein kinase domain consists of a bi-lobed structure that 
is similar to that of all other protein kinases. FGFR gene alterations occur in 
a wide variety of cancers including those of the urinary bladder, breast, ovary, 
prostate, endometrium, lung, and stomach. The majority (66 %) of FGFR gene 
alterations involve gene amplifications, followed by mutations (26 %), and 
rearrangements that produce fusion proteins (8 %). Erdafitinib was the first 
orally effective FGFR antagonist approved by the FDA (2019) for the treatment of 
advanced cancer, that of the urinary bladder. FGF23 suppresses phosphate 
reabsorption in the proximal tubules of the kidney; FGF23 blockade allows 
phosphate reabsorption to occur and leads to elevated serum phosphate levels. 
Erdafitinib and several other, but not all, FGFR antagonists produce 
hyperphosphatemia. Erdafitinib binds to an inactive DGF-Din conformation of 
FGFR1 and is classified as a type I½ inhibitor. Similarly, dovitinib, AZD4547, 
CH5183284, infigratinib, lenvatinib, LY2874455, and lucitanib are type I½ 
inhibitors. The inactive conformations contain an autoinhibitory brake that is 
made up of three main residues: an asparagine (N) within the αC-β4 back loop, a 
glutamate (E) corresponding to the second hinge residue, and a lysine (K) in the 
β8-strand (the NEK triad). PDGFRα/β, Kit, CSF1R, VEGFR1/2/3, Flt3, Tek, and Tie 
protein kinases are also regulated by a similar autoinhibitory brake mechanism. 
Ponatinib binds to FGFR4 in a DFG-Dout conformation and is classified as a type 
II inhibitor. Futibatinib, roblitinib, H3B-6527, fisogatinib, and PRN1371 bind 
covalently to their FGFR target and are classified as type VI inhibitors. 
Nintedanib, pazopanib, pemigatinib, rogaratinib, fisogatinib, and PRN1371 are 
FGFR inhibitors lacking drug-enzyme crystal structures. All of the 
aforementioned FGFR antagonists are orally effective. The development of FGFR 
inhibitors has lagged behind those of other receptor protein-tyrosine kinases. 
However, the FDA approval of erdafitinib for the treatment of urinary bladder 
cancers may stimulate additional work targeting the many other FGFR-driven 
neoplasms.