PDBsum entry 3dpk

Transferase

PDB id: 3dpk

Contents

Protein chain

279 a.a. *

Ligands

SO4 ×3

8C5

Waters ×123

* Residue conservation analysis

PDB id:

3dpk

Name:

Transferase

Title:

Cfms tyrosine kinase in complex with a pyridopyrimidinone inhibitor

Structure:

Macrophage colony-stimulating factor 1 receptor, fibroblast growth factor receptor 1. Chain: a. Fragment: kinase domain. Synonym: csf-1 receptor, csf-1-r, csf-1r, m-csf-r, proto-oncogenE C- fms, fgfr-1, basic fibroblast growth factor receptor 1, bfgfr, bfgf- r-1, fms-like tyrosine kinase 2, flt-2, n-sam, proto-oncogenE C-fgr. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: csf1r, fgfbr, fgfr1, flg, flt2, fms, bfgfr, cek, hbgfr. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.95Å R-factor: 0.192 R-free: 0.244

Authors:

C.Schubert

Key ref:

H.Huang et al. (2009). Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors. J Med Chem, 52, 1081-1099. PubMed id: 19193011

Date:

08-Jul-08 Release date: 17-Feb-09

Protein chain

P07333  (CSF1R_HUMAN) -  Macrophage colony-stimulating factor 1 receptor from Homo sapiens

Seq: 972 a.a.

Struc: 279 a.a.*

Protein chain

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

Seq: 822 a.a.

Struc: 279 a.a.*

* PDB and UniProt seqs differ at 135 residue positions (black crosses)

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

J Med Chem 52:1081-1099 (2009)

PubMed id: 19193011

Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors.

H.Huang, D.A.Hutta, J.M.Rinker, H.Hu, W.H.Parsons, C.Schubert, R.L.DesJarlais, C.S.Crysler, M.A.Chaikin, R.R.Donatelli, Y.Chen, D.Cheng, Z.Zhou, E.Yurkow, C.L.Manthey, M.R.Player.

ABSTRACT

A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.