3DPK

cFMS tyrosine kinase in complex with a pyridopyrimidinone inhibitor

Summary for 3DPK

• Entry DOI: 10.2210/pdb3dpk/pdb
• Related: 2i0v 2i1m 2ogv 3bea
• Descriptor: Macrophage colony-stimulating factor 1 receptor, Fibroblast growth factor receptor 1, SULFATE ION, 8-cyclohexyl-N-methoxy-5-oxo-2-{[4-(2-pyrrolidin-1-ylethyl)phenyl]amino}-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxamide, ... (4 entities in total)
• Functional Keywords: receptor tyrosine kinase, kinase-inhibitor complex, atp-binding, glycoprotein, immunoglobulin domain, kinase, membrane, nucleotide-binding, phosphoprotein, proto-oncogene, receptor, transferase, transmembrane, tyrosine-protein kinase, craniosynostosis, disease mutation, dwarfism, heparin-binding, kallmann syndrome
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Single-pass type I membrane protein: P07333
• Total number of polymer chains: 1
• Total formula weight: 38843.26

Authors

Schubert, C. (deposition date: 2008-07-08, release date: 2009-02-17, Last modification date: 2023-08-30)

Primary citation

Huang, H.,Hutta, D.A.,Rinker, J.M.,Hu, H.,Parsons, W.H.,Schubert, C.,DesJarlais, R.L.,Crysler, C.S.,Chaikin, M.A.,Donatelli, R.R.,Chen, Y.,Cheng, D.,Zhou, Z.,Yurkow, E.,Manthey, C.L.,Player, M.R.
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, 2009

PubMed 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.

PubMed: 19193011
DOI: 10.1021/jm801406h

Experimental method

X-RAY DIFFRACTION (1.95 Å)