4HW7

Crystal structure of FMS kinase domain with a small molecular inhibitor, PLX647-OME

Summary for 4HW7

• Entry DOI: 10.2210/pdb4hw7/pdb
• Descriptor: Macrophage colony-stimulating factor 1 receptor, 5-[(5-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-N-[4-(trifluoromethyl)benzyl]pyridin-2-amine (2 entities in total)
• Functional Keywords: csf-1-r, fms proto-oncogene, c-fms, cd115 antigen, kinase, atp-binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein: P07333
• Total number of polymer chains: 1
• Total formula weight: 39052.58

Authors

Zhang, Y.,Zhang, C. (deposition date: 2012-11-07, release date: 2013-03-27, Last modification date: 2024-02-28)

Primary citation

Zhang, C.,Ibrahim, P.N.,Zhang, J.,Burton, E.A.,Habets, G.,Zhang, Y.,Powell, B.,West, B.L.,Matusow, B.,Tsang, G.,Shellooe, R.,Carias, H.,Nguyen, H.,Marimuthu, A.,Zhang, K.Y.,Oh, A.,Bremer, R.,Hurt, C.R.,Artis, D.R.,Wu, G.,Nespi, M.,Spevak, W.,Lin, P.,Nolop, K.,Hirth, P.,Tesch, G.H.,Bollag, G.
Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor.
Proc.Natl.Acad.Sci.USA, 110:5689-5694, 2013

PubMed 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.

PubMed: 23493555
DOI: 10.1073/pnas.1219457110

Experimental method

X-RAY DIFFRACTION (2.9001 Å)