Inhibitors of the Fibroblast Growth Factor Receptor

Abstract

Signaling through the fibroblast growth factor receptor (FGFR) tyrosine kinase is crucial to a number of key pharmacological processes; however, dysregulation of this signaling is observed with a number of different cancers suggesting that inhibition of FGFR may provide an important therapeutic agent in the treatment of cancers. This chapter provides an overview of the development of FGFR inhibitors beginning with the identification of nonselective FGFR inhibitors, then describing the medicinal chemistry optimization resulting in the delivery of a number of highly selective FGFR inhibitors, some of which are currently being assessed in clinical trials. The development of isoform selective FGFR inhibitors as well as covalent inhibitors and inhibitors of the inactive form of FGFR are also described.

Development of Highly Potent and Selective FGFR4 Inhibitors Based on SNAr Electrophiles

“…[53,54] The following chlorination of the electron-rich dimethoxyphenyl system in the obtained intermediates 10A and 11A was carried out by the addition of sulfuryl chloride in acetonitrile (ACN) at -20 °C in a moderate to very high yield. [55] Amination of the quinazoline scaffold of 2chloroquinazolines 10A and 10B was achieved by treatment with aqueous ammonia solution in 1,4-dioxane in a microwave reactor at 100 °C in a very high yield. Finally, https://doi.org/10.26434/chemrxiv-2024-n89hr ORCID: https://orcid.org/0000-0003-0163-3419 Content not peer-reviewed by ChemRxiv.…”

Indolin-2-one derivatives as selective Aurora B kinase inhibitors targeting breast cancer

“…Considering the efficacy of the pyrrole indolin-2-one unit as a hinge binder [27][28][29], we utilized the ChEMBL database to identify pyrrole indolinone-based kinase inhibitors with reported activity against Aurora B [30]. A previously reported Chk1 kinase inhibitor, (Z)-3-((1Hpyrrol-2-yl)methylene)-6-(4-hydroxyphenyl)indolin-2-one (1) [31] (Figure 1) showing potent activity against Aurora B kinase (Ki = 19.95 nM) was identified and selected as a lead compound.…”