Discovery of N-(4-((6-(3,5- Dimethoxyphenyl)-9H-purine derivatives as irreversible covalent FGFR inhibitors

Eur J Med Chem. 2024 Apr 17;271:116415. doi: 10.1016/j.ejmech.2024.116415. Online ahead of print.ABSTRACTFibroblast growth factor receptor (FGFR) is an attractive target for cancer therapy, but existing FGFR inhibitors appear to hardly meet the demand for clinical application. Herein, a number of irreversible covalent FGFR inhibitors were designed and synthesized by selecting several five- and six-membered azaheterocycles as parent scaffold with different substituents to take over the hydrophobic region in the active pocket of FGFR proteins. Among the resulting target compounds, III-30 showed the most potent effect on enzyme activity inhibition and anti-proliferative activity against the tested cancer cell lines. Significantly, III-30 could inhibit the enzyme activity by achieving irreversible covalent binding with FGFR1 and FGFR4 proteins. It could also regulate FGFR-mediated signaling pathway and mitochondrial apoptotic pathway to promote cancer cell apoptosis and inhibit cancer cell invasion and metastasis. Moreover, III-30 had a good metabolic stability and showed relatively potent anti-tumor activity in the MDA-MB-231 xenograft tumor mice model.PMID:38643670 | DOI:10.1016/j.ejmech.2024.116415
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Source Type: research