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{{STRUCTURE_4hw7|  PDB=4hw7  |  SCENE=  }}
==Crystal structure of FMS kinase domain with a small molecular inhibitor, PLX647-OME==
===Crystal structure of FMS kinase domain with a small molecular inhibitor, PLX647-OME===
<StructureSection load='4hw7' size='340' side='right' caption='[[4hw7]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
{{ABSTRACT_PUBMED_23493555}}
== Structural highlights ==
 
<table><tr><td colspan='2'>[[4hw7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HW7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HW7 FirstGlance]. <br>
==Disease==
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=64M:5-[(5-METHOXY-1H-PYRROLO[2,3-B]PYRIDIN-3-YL)METHYL]-N-[4-(TRIFLUOROMETHYL)BENZYL]PYRIDIN-2-AMINE'>64M</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CSF1R, FMS ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4hw7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hw7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4hw7 RCSB], [http://www.ebi.ac.uk/pdbsum/4hw7 PDBsum]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/CSF1R_HUMAN CSF1R_HUMAN]] Note=Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers.<ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:16337366</ref>  Note=Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection.<ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:16337366</ref>  Defects in CSF1R are the cause of leukoencephalopathy, diffuse hereditary, with spheroids (HDLS) [MIM:[http://omim.org/entry/221820 221820]]. An autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes.<ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:16337366</ref> <ref>PMID:22197934</ref>   
[[http://www.uniprot.org/uniprot/CSF1R_HUMAN CSF1R_HUMAN]] Note=Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers.<ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:16337366</ref>  Note=Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection.<ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:16337366</ref>  Defects in CSF1R are the cause of leukoencephalopathy, diffuse hereditary, with spheroids (HDLS) [MIM:[http://omim.org/entry/221820 221820]]. An autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes.<ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:16337366</ref> <ref>PMID:22197934</ref>   
 
== Function ==
==Function==
[[http://www.uniprot.org/uniprot/CSF1R_HUMAN CSF1R_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor.<ref>PMID:7683918</ref> <ref>PMID:12882960</ref> <ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:16170366</ref> <ref>PMID:18467591</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:20489731</ref> <ref>PMID:20829061</ref> <ref>PMID:20504948</ref> <ref>PMID:16337366</ref> <ref>PMID:19193011</ref>   
[[http://www.uniprot.org/uniprot/CSF1R_HUMAN CSF1R_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor.<ref>PMID:7683918</ref> <ref>PMID:12882960</ref> <ref>PMID:15117969</ref> <ref>PMID:16648572</ref> <ref>PMID:17121910</ref> <ref>PMID:16170366</ref> <ref>PMID:18467591</ref> <ref>PMID:18814279</ref> <ref>PMID:19934330</ref> <ref>PMID:20489731</ref> <ref>PMID:20829061</ref> <ref>PMID:20504948</ref> <ref>PMID:16337366</ref> <ref>PMID:19193011</ref>   
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.


==About this Structure==
Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor.,Zhang C, Ibrahim PN, Zhang J, Burton EA, Habets G, Zhang Y, Powell B, West BL, Matusow B, Tsang G, Shellooe R, Carias H, Nguyen H, Marimuthu A, Zhang KY, Oh A, Bremer R, Hurt CR, Artis DR, Wu G, Nespi M, Spevak W, Lin P, Nolop K, Hirth P, Tesch GH, Bollag G Proc Natl Acad Sci U S A. 2013 Mar 14. PMID:23493555<ref>PMID:23493555</ref>
[[4hw7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HW7 OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
<references group="xtra"/><references/>
</div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Zhang, C.]]
[[Category: Zhang, C]]
[[Category: Zhang, Y.]]
[[Category: Zhang, Y]]
[[Category: Atp-binding]]
[[Category: Atp-binding]]
[[Category: C-fm]]
[[Category: C-fm]]

Revision as of 16:44, 4 January 2015

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

Structural highlights

4hw7 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:CSF1R, FMS (Homo sapiens)
Activity:Receptor protein-tyrosine kinase, with EC number 2.7.10.1
Resources:FirstGlance, OCA, RCSB, PDBsum

Disease

[CSF1R_HUMAN] Note=Aberrant expression of CSF1 or CSF1R can promote cancer cell proliferation, invasion and formation of metastases. Overexpression of CSF1 or CSF1R is observed in a significant percentage of breast, ovarian, prostate, and endometrial cancers.[1] [2] [3] [4] [5] [6] Note=Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection.[7] [8] [9] [10] [11] [12] Defects in CSF1R are the cause of leukoencephalopathy, diffuse hereditary, with spheroids (HDLS) [MIM:221820]. An autosomal dominant adult-onset rapidly progressive neurodegenerative disorder characterized by variable behavioral, cognitive, and motor changes. Patients often die of dementia within 6 years of onset. Brain imaging shows patchy abnormalities in the cerebral white matter, predominantly affecting the frontal and parietal lobes.[13] [14] [15] [16] [17] [18] [19]

Function

[CSF1R_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes, such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1, and thereby plays an important role in innate immunity and in inflammatory processes. Plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. Required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Promotes reorganization of the actin cytoskeleton, regulates formation of membrane ruffles, cell adhesion and cell migration, and promotes cancer cell invasion. Activates several signaling pathways in response to ligand binding. Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, that then lead to the activation of protein kinase C family members, especially PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1, and of the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals both via proteins that directly interact with phosphorylated tyrosine residues in its intracellular domain, or via adapter proteins, such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. Receptor signaling is down-regulated by protein phosphatases, such as INPP5D/SHIP-1, that dephosphorylate the receptor and its downstream effectors, and by rapid internalization of the activated receptor.[20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33]

Publication Abstract from PubMed

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.

Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor.,Zhang C, Ibrahim PN, Zhang J, Burton EA, Habets G, Zhang Y, Powell B, West BL, Matusow B, Tsang G, Shellooe R, Carias H, Nguyen H, Marimuthu A, Zhang KY, Oh A, Bremer R, Hurt CR, Artis DR, Wu G, Nespi M, Spevak W, Lin P, Nolop K, Hirth P, Tesch GH, Bollag G Proc Natl Acad Sci U S A. 2013 Mar 14. PMID:23493555[34]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. PMID:15117969 doi:10.1083/jcb.200309102
  2. ↑ Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. PMID:16648572 doi:10.1158/1535-7163.MCT-05-0359
  3. ↑ Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T, Isoe T. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43. PMID:17121910 doi:10.1158/1535-7163.MCT-05-0313
  4. ↑ Hiraga T, Nakamura H. Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals. Int J Cancer. 2009 Jan 1;124(1):215-22. doi: 10.1002/ijc.23903. PMID:18814279 doi:10.1002/ijc.23903
  5. ↑ Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009 Dec 15;69(24):9498-506. doi: 10.1158/0008-5472.CAN-09-1868. Epub, . PMID:19934330 doi:10.1158/0008-5472.CAN-09-1868
  6. ↑ Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Epub 2005 Dec 6. PMID:16337366 doi:10.1016/j.coi.2005.11.006
  7. ↑ Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. PMID:15117969 doi:10.1083/jcb.200309102
  8. ↑ Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. PMID:16648572 doi:10.1158/1535-7163.MCT-05-0359
  9. ↑ Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T, Isoe T. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43. PMID:17121910 doi:10.1158/1535-7163.MCT-05-0313
  10. ↑ Hiraga T, Nakamura H. Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals. Int J Cancer. 2009 Jan 1;124(1):215-22. doi: 10.1002/ijc.23903. PMID:18814279 doi:10.1002/ijc.23903
  11. ↑ Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009 Dec 15;69(24):9498-506. doi: 10.1158/0008-5472.CAN-09-1868. Epub, . PMID:19934330 doi:10.1158/0008-5472.CAN-09-1868
  12. ↑ Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Epub 2005 Dec 6. PMID:16337366 doi:10.1016/j.coi.2005.11.006
  13. ↑ Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. PMID:15117969 doi:10.1083/jcb.200309102
  14. ↑ Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. PMID:16648572 doi:10.1158/1535-7163.MCT-05-0359
  15. ↑ Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T, Isoe T. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43. PMID:17121910 doi:10.1158/1535-7163.MCT-05-0313
  16. ↑ Hiraga T, Nakamura H. Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals. Int J Cancer. 2009 Jan 1;124(1):215-22. doi: 10.1002/ijc.23903. PMID:18814279 doi:10.1002/ijc.23903
  17. ↑ Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009 Dec 15;69(24):9498-506. doi: 10.1158/0008-5472.CAN-09-1868. Epub, . PMID:19934330 doi:10.1158/0008-5472.CAN-09-1868
  18. ↑ Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Epub 2005 Dec 6. PMID:16337366 doi:10.1016/j.coi.2005.11.006
  19. ↑ Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, Lash J, Wider C, Wojtas A, DeJesus-Hernandez M, Adamson J, Kouri N, Sundal C, Shuster EA, Aasly J, MacKenzie J, Roeber S, Kretzschmar HA, Boeve BF, Knopman DS, Petersen RC, Cairns NJ, Ghetti B, Spina S, Garbern J, Tselis AC, Uitti R, Das P, Van Gerpen JA, Meschia JF, Levy S, Broderick DF, Graff-Radford N, Ross OA, Miller BB, Swerdlow RH, Dickson DW, Wszolek ZK. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet. 2011 Dec 25;44(2):200-5. doi: 10.1038/ng.1027. PMID:22197934 doi:10.1038/ng.1027
  20. ↑ Bourette RP, Mouchiroud G, Ouazana R, Morle F, Godet J, Blanchet JP. Expression of human colony-stimulating factor-1 (CSF-1) receptor in murine pluripotent hematopoietic NFS-60 cells induces long-term proliferation in response to CSF-1 without loss of erythroid differentiation potential. Blood. 1993 May 15;81(10):2511-20. PMID:7683918
  21. ↑ Baran CP, Tridandapani S, Helgason CD, Humphries RK, Krystal G, Marsh CB. The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity. J Biol Chem. 2003 Oct 3;278(40):38628-36. Epub 2003 Jul 25. PMID:12882960 doi:10.1074/jbc.M305021200
  22. ↑ Wrobel CN, Debnath J, Lin E, Beausoleil S, Roussel MF, Brugge JS. Autocrine CSF-1R activation promotes Src-dependent disruption of mammary epithelial architecture. J Cell Biol. 2004 Apr 26;165(2):263-73. PMID:15117969 doi:10.1083/jcb.200309102
  23. ↑ Guo J, Marcotte PA, McCall JO, Dai Y, Pease LJ, Michaelides MR, Davidsen SK, Glaser KB. Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors. Mol Cancer Ther. 2006 Apr;5(4):1007-13. PMID:16648572 doi:10.1158/1535-7163.MCT-05-0359
  24. ↑ Ohno H, Kubo K, Murooka H, Kobayashi Y, Nishitoba T, Shibuya M, Yoneda T, Isoe T. A c-fms tyrosine kinase inhibitor, Ki20227, suppresses osteoclast differentiation and osteolytic bone destruction in a bone metastasis model. Mol Cancer Ther. 2006 Nov;5(11):2634-43. PMID:17121910 doi:10.1158/1535-7163.MCT-05-0313
  25. ↑ Taylor JR, Brownlow N, Domin J, Dibb NJ. FMS receptor for M-CSF (CSF-1) is sensitive to the kinase inhibitor imatinib and mutation of Asp-802 to Val confers resistance. Oncogene. 2006 Jan 5;25(1):147-51. PMID:16170366 doi:10.1038/sj.onc.1209007
  26. ↑ Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E, Halenbeck R, Wu G, Zhou A, Behrens D, Hollenbaugh D, Linnemann T, Qin M, Wong J, Chu K, Doberstein SK, Williams LT. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science. 2008 May 9;320(5877):807-11. doi: 10.1126/science.1154370. PMID:18467591 doi:10.1126/science.1154370
  27. ↑ Hiraga T, Nakamura H. Imatinib mesylate suppresses bone metastases of breast cancer by inhibiting osteoclasts through the blockade of c-Fms signals. Int J Cancer. 2009 Jan 1;124(1):215-22. doi: 10.1002/ijc.23903. PMID:18814279 doi:10.1002/ijc.23903
  28. ↑ Patsialou A, Wyckoff J, Wang Y, Goswami S, Stanley ER, Condeelis JS. Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 2009 Dec 15;69(24):9498-506. doi: 10.1158/0008-5472.CAN-09-1868. Epub, . PMID:19934330 doi:10.1158/0008-5472.CAN-09-1868
  29. ↑ Chihara T, Suzu S, Hassan R, Chutiwitoonchai N, Hiyoshi M, Motoyoshi K, Kimura F, Okada S. IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation. Cell Death Differ. 2010 Dec;17(12):1917-27. doi: 10.1038/cdd.2010.60. Epub 2010, May 21. PMID:20489731 doi:10.1038/cdd.2010.60
  30. ↑ Eda H, Zhang J, Keith RH, Michener M, Beidler DR, Monahan JB. Macrophage-colony stimulating factor and interleukin-34 induce chemokines in human whole blood. Cytokine. 2010 Dec;52(3):215-20. doi: 10.1016/j.cyto.2010.08.005. Epub 2010 Sep, 9. PMID:20829061 doi:10.1016/j.cyto.2010.08.005
  31. ↑ Wei S, Nandi S, Chitu V, Yeung YG, Yu W, Huang M, Williams LT, Lin H, Stanley ER. Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol. 2010 Sep;88(3):495-505. doi: 10.1189/jlb.1209822. Epub 2010 May, 26. PMID:20504948 doi:10.1189/jlb.1209822
  32. ↑ Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol. 2006 Feb;18(1):39-48. Epub 2005 Dec 6. PMID:16337366 doi:10.1016/j.coi.2005.11.006
  33. ↑ Huang H, Hutta DA, Rinker JM, Hu H, Parsons WH, Schubert C, Desjarlais RL, Crysler CS, Chaikin MA, Donatelli RR, Chen Y, Cheng D, Zhou Z, Yurkow E, Manthey CL, Player MR. Pyrido[2,3-d]pyrimidin-5-ones: A Novel Class of Antiinflammatory Macrophage Colony-Stimulating Factor-1 Receptor Inhibitors (dagger). J Med Chem. 2009 Feb 4. PMID:19193011 doi:10.1021/jm801406h
  34. ↑ Zhang C, Ibrahim PN, Zhang J, Burton EA, Habets G, Zhang Y, Powell B, West BL, Matusow B, Tsang G, Shellooe R, Carias H, Nguyen H, Marimuthu A, Zhang KY, Oh A, Bremer R, Hurt CR, Artis DR, Wu G, Nespi M, Spevak W, Lin P, Nolop K, Hirth P, Tesch GH, Bollag G. Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor. Proc Natl Acad Sci U S A. 2013 Mar 14. PMID:23493555 doi:http://dx.doi.org/10.1073/pnas.1219457110

4hw7, resolution 2.90Å

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