PDBsum entry 4hw7

Transferase/transferase inhibitor

PDB id: 4hw7

Contents

Protein chain

289 a.a.

Ligands

64M

PDB id:

4hw7

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of fms kinase domain with a small molecular inhibitor, plx647-ome

Structure:

Macrophage colony-stimulating factor 1 receptor. Chain: a. Fragment: fms kinase domain with kid. Synonym: csf-1 receptor, csf-1-r, csf-1r, m-csf-r, proto-oncogenE C- fms. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: csf1r, fms. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.90Å R-factor: 0.222 R-free: 0.267

Authors:

Y.Zhang,C.Zhang

Key ref:

C.Zhang et al. (2013). Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor. Proc Natl Acad Sci U S A, 110, 5689-5694. PubMed id: 23493555 DOI: 10.1073/pnas.1219457110

Date:

07-Nov-12 Release date: 27-Mar-13

Protein chain

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

Seq: 972 a.a.

Struc: 289 a.a.*

* PDB and UniProt seqs differ at 3 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

DOI no: 10.1073/pnas.1219457110

Proc Natl Acad Sci U S A 110:5689-5694 (2013)

PubMed id: 23493555

Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor.

C.Zhang, P.N.Ibrahim, J.Zhang, E.A.Burton, G.Habets, Y.Zhang, B.Powell, B.L.West, B.Matusow, G.Tsang, R.Shellooe, H.Carias, H.Nguyen, A.Marimuthu, K.Y.Zhang, A.Oh, R.Bremer, C.R.Hurt, D.R.Artis, G.Wu, M.Nespi, W.Spevak, P.Lin, K.Nolop, P.Hirth, G.H.Tesch, G.Bollag.

ABSTRACT

Inflammation and cancer, two therapeutic areas historically addressed by separate drug discovery efforts, are now coupled in treatment approaches by a growing understanding of the dynamic molecular dialogues between immune and cancer cells. Agents that target specific compartments of the immune system, therefore, not only bring new disease modifying modalities to inflammatory diseases, but also offer a new avenue to cancer therapy by disrupting immune components of the microenvironment that foster tumor growth, progression, immune evasion, and treatment resistance. McDonough feline sarcoma viral (v-fms) oncogene homolog (FMS) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) are two hematopoietic cell surface receptors that regulate the development and function of macrophages and mast cells, respectively. We disclose a highly specific dual FMS and KIT kinase inhibitor developed from a multifaceted chemical scaffold. As expected, this inhibitor blocks the activation of macrophages, osteoclasts, and mast cells controlled by these two receptors. More importantly, the dual FMS and KIT inhibition profile has translated into a combination of benefits in preclinical disease models of inflammation and cancer.