5UR1

FGFR1 kinase domain complex with SN37333 in reversible binding mode

Summary for 5UR1

• Entry DOI: 10.2210/pdb5ur1/pdb
• Related: 5UOK 5UOL 5UOM 5UON
• Descriptor: Fibroblast growth factor receptor 1, 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{1-[4-(dimethylamino)but-2-enoyl]piperidin-4-yl}-7-(phenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (3 entities in total)
• Functional Keywords: transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Single-pass type I membrane protein: P11362
• Total number of polymer chains: 2
• Total formula weight: 71988.35

Authors

Yosaatmadja, Y.,Paik, W.-K.,Smaill, J.B.,Squire, C.J. (deposition date: 2017-02-09, release date: 2017-05-31, Last modification date: 2023-10-04)

Primary citation

Li, X.,Guise, C.P.,Taghipouran, R.,Yosaatmadja, Y.,Ashoorzadeh, A.,Paik, W.K.,Squire, C.J.,Jiang, S.,Luo, J.,Xu, Y.,Tu, Z.C.,Lu, X.,Ren, X.,Patterson, A.V.,Smaill, J.B.,Ding, K.
2-Oxo-3, 4-dihydropyrimido[4, 5-d]pyrimidinyl derivatives as new irreversible pan fibroblast growth factor receptor (FGFR) inhibitors.
Eur J Med Chem, 135:531-543, 2017

PubMed Abstract: A series of 2-oxo-3, 4-dihydropyrimido[4,5-d]-pyrimidinyl derivatives were designed and synthesized as new irreversible inhibitors of the FGFR family. One of the most promising compounds 2l potently inhibited FGFR1/2/3 with IC values of 1.06, 0.84 and 5.38 nM, respectively, whereas its potency against FGFR4 was diminished by an order of magnitude. Compound 2l strongly suppresses the proliferation of FGFR1-amplified H520 non-small cell lung cancer cells, FGFR2-amplified SUM52 breast cancer cells and FGFR3-amplified SW780 bladder cancer cells with low nanomolar IC values, but was significantly less potent against four FGFR-negative cancer cell lines, with low micromolar IC values. Biological investigation also confirmed the irreversible binding of the molecule with the FGFR1-3 target kinases. Compound 2l may serve as a promising new lead for further anticancer drug discovery.

PubMed: 28521156
DOI: 10.1016/j.ejmech.2017.04.049

Experimental method

X-RAY DIFFRACTION (2.2 Å)