6IUO

Crystal structure of FGFR4 kinase domain in complex with a covalent inhibitor

Summary for 6IUO

• Entry DOI: 10.2210/pdb6iuo/pdb
• Descriptor: Fibroblast growth factor receptor 4, N-({4-[4-amino-3-(3,5-dimethyl-1-benzofuran-2-yl)-7-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-2-yl]phenyl}methyl)prop-2-enamide (3 entities in total)
• Functional Keywords: protein kinase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 36417.86

Authors

Xu, Y.,Liu, Q. (deposition date: 2018-11-29, release date: 2019-10-23, Last modification date: 2024-10-16)

Primary citation

Wang, Y.,Dai, Y.,Wu, X.,Li, F.,Liu, B.,Li, C.,Liu, Q.,Zhou, Y.,Wang, B.,Zhu, M.,Cui, R.,Tan, X.,Xiong, Z.,Liu, J.,Tan, M.,Xu, Y.,Geng, M.,Jiang, H.,Liu, H.,Ai, J.,Zheng, M.
Discovery and Development of a Series of Pyrazolo[3,4-d]pyridazinone Compounds as the Novel Covalent Fibroblast Growth Factor Receptor Inhibitors by the Rational Drug Design.
J.Med.Chem., 62:7473-7488, 2019

PubMed Abstract: Alterations of fibroblast growth factor receptors (FGFRs) play key roles in numerous cancer progression and development, which makes FGFRs attractive targets in the cancer therapy. In the present study, based on a newly devised FGFR target-specific scoring function, a novel FGFR inhibitor hit was identified through virtual screening. Hit-to-lead optimization was then performed by integrating molecular docking and site-of-metabolism predictions with an array of in vitro evaluations and X-ray cocrystal structure determination, leading to a covalent FGFR inhibitor , which showed a highly selective and potent FGFR inhibition profile. Pharmacokinetic assessment, protein kinase profiling, and hERG inhibition evaluation were also conducted, and they confirmed the value of as a lead for further investigation. Overall, this study exemplifies the importance of the integrative use of computational methods and experimental techniques in drug discovery.

PubMed: 31335138
DOI: 10.1021/acs.jmedchem.9b00510

Experimental method

X-RAY DIFFRACTION (2.3 Å)