PDBsum entry 6itj

Transferase/inhibitor

PDB id: 6itj

Contents

Protein chains

290 a.a.

Ligands

AXU ×2

Waters ×238

PDB id:

6itj

Name:

Transferase/inhibitor

Title:

Crystal structure of fgfr1 kinase domain in complex with compound 3

Structure:

Fibroblast growth factor receptor 1. Chain: a, b. Fragment: unp residues 458-765. Synonym: fgfr-1,basic fibroblast growth factor receptor 1,bfgf-r-1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fgfr1. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.99Å R-factor: 0.201 R-free: 0.244

Authors:

Y.Xu,Q.Liu

Key ref:

Y.Wang et al. (2019). 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. PubMed id: 31335138 DOI: 10.1021/acs.jmedchem.9b00510

Date:

23-Nov-18 Release date: 23-Oct-19

Protein chains

P11362  (FGFR1_HUMAN) -  Fibroblast growth factor receptor 1 from Homo sapiens

Seq: 822 a.a.

Struc: 290 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/acs.jmedchem.9b00510

J Med Chem 62:7473-7488 (2019)

PubMed id: 31335138

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.

Y.Wang, Y.Dai, X.Wu, F.Li, B.Liu, C.Li, Q.Liu, Y.Zhou, B.Wang, M.Zhu, R.Cui, X.Tan, Z.Xiong, J.Liu, M.Tan, Y.Xu, M.Geng, H.Jiang, H.Liu, J.Ai, M.Zheng.

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 15, 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 15 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.