View source for 6gqm


==Crystal structure of human c-KIT kinase domain in complex with a small molecule inhibitor, AZD3229==
<StructureSection load='6gqm' size='340' side='right' caption='[[6gqm]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6gqm]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6GQM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6GQM FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=F8H:~{N}-[4-[[5-fluoranyl-7-(2-methoxyethoxy)quinazolin-4-yl]amino]phenyl]-2-(4-propan-2-yl-1,2,3-triazol-1-yl)ethanamide'>F8H</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KIT, SCFR ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6gqm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6gqm OCA], [http://pdbe.org/6gqm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6gqm RCSB], [http://www.ebi.ac.uk/pdbsum/6gqm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6gqm ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Defects in KIT are a cause of piebald trait (PBT) [MIM:[http://omim.org/entry/172800 172800]]; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes.<ref>PMID:1376329</ref> <ref>PMID:1370874</ref> <ref>PMID:1717985</ref> <ref>PMID:7687267</ref> <ref>PMID:8680409</ref> <ref>PMID:9029028</ref> <ref>PMID:9450866</ref> <ref>PMID:9699740</ref> <ref>PMID:11074500</ref>   Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:[http://omim.org/entry/606764 606764]].<ref>PMID:9029028</ref> <ref>PMID:9697690</ref> <ref>PMID:9438854</ref> <ref>PMID:11505412</ref> <ref>PMID:15824741</ref>   Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:[http://omim.org/entry/273300 273300]]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.<ref>PMID:9029028</ref>   Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:[http://omim.org/entry/601626 601626]]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase.<ref>PMID:9029028</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.<ref>PMID:7520444</ref> <ref>PMID:9528781</ref> <ref>PMID:10397721</ref> <ref>PMID:12444928</ref> <ref>PMID:12878163</ref> <ref>PMID:12511554</ref> <ref>PMID:17904548</ref> <ref>PMID:19265199</ref> <ref>PMID:21640708</ref> <ref>PMID:21135090</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
While the treatment of Gastrointestinal Stromal Tumors (GIST) has been revolutionised by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multi-targeted agents. This effort focussed on identification and optimisation of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFR, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimised, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalised predominantly by the interaction of water molecules with the protein and ligand in the active site and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.

Discovery of N-{4-[(6,7-dimethoxyquinazolin-4-yl)oxy]phenyl}-2-[4-(propan-2-yl)-1H-1,2,3-triaz ol-1-yl]acetamide (AZD3229), a potent pan-KIT mutant inhibitor for the treatment of gastrointestinal stromal tumors.,Kettle JG, Anjum R, Barry E, Bhavsar D, Brown C, Boyd S, Campbell A, Goldberg K, Grondine M, Guichard S, Hardy C, Hunt T, Jones R, Li X, Moleva O, Ogg D, Overman R, Packer MJ, Pearson S, Schimpl M, Shao W, Smith A, Smith J, Stead D, Stokes S, Tucker M, Ye Y J Med Chem. 2018 Sep 11. doi: 10.1021/acs.jmedchem.8b00938. PMID:30204441<ref>PMID:30204441</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6gqm" style="background-color:#fffaf0;"></div>

==See Also==
*[[Tyrosine kinase|Tyrosine kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Anjum, R]]
[[Category: Barry, E]]
[[Category: Bhavsar, D]]
[[Category: Brown, C]]
[[Category: Campbell, A]]
[[Category: Goldberg, K]]
[[Category: Grondine, M]]
[[Category: Guichard, S]]
[[Category: Hardy, C J]]
[[Category: Hunt, T]]
[[Category: Jones, O]]
[[Category: Kettle, J G]]
[[Category: Li, X]]
[[Category: Moleva, O]]
[[Category: Ogg, D J]]
[[Category: Overman, R C]]
[[Category: Packer, M J]]
[[Category: Pearson, S]]
[[Category: Schimpl, M]]
[[Category: Shao, W]]
[[Category: Smith, A]]
[[Category: Smith, J]]
[[Category: Stead, D]]
[[Category: Stokes, S]]
[[Category: Tucker, M]]
[[Category: Ye, Y]]
[[Category: Gastrointestinal stromal tumour]]
[[Category: Inhibitor]]
[[Category: Oncology]]
[[Category: Receptor tyrosine kinase]]
[[Category: Signaling protein]]
[[Category: Structure-based drug design]]