The role of fibroblast growth factor receptor (FGFR) protein-tyrosine kinase inhibitors in the treatment of cancers including those of the urinary bladder.

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Roskoski R Jr

The role of fibroblast growth factor receptor (FGFR) protein-tyrosine kinase inhibitors in the treatment of cancers including those of the urinary bladder.

Pharmacol Res. 2020 Jan;151:104567. doi: 10.1016/j.phrs.2019.104567. Epub 2019 Nov 23.

PubMed ID
31770593 [ View in PubMed
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Abstract

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 I(1/2) inhibitor. Similarly, dovitinib, AZD4547, CH5183284, infigratinib, lenvatinib, LY2874455, and lucitanib are type I(1/2) inhibitors. The inactive conformations contain an autoinhibitory brake that is made up of three main residues: an asparagine (N) within the alphaC-beta4 back loop, a glutamate (E) corresponding to the second hinge residue, and a lysine (K) in the beta8-strand (the NEK triad). PDGFRalpha/beta, 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.

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