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[[Image:4agw.jpg|left|200px]]
==Discovery of a small molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases==
<StructureSection load='4agw' size='340' side='right' caption='[[4agw]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4agw]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AGW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4AGW FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=NG7:3-{2-[(CYCLOPROPYLCARBONYL)AMINO][1,3]THIAZOLO[5,4-B]PYRIDIN-5-YL}-N-{4-[(4-ETHYLPIPERAZIN-1-YL)METHYL]-3-(TRIFLUOROMETHYL)PHENYL}BENZAMIDE'>NG7</scene><br>
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1prm|1prm]], [[1prl|1prl]], [[1rlq|1rlq]], [[1f1w|1f1w]], [[1p13|1p13]], [[1srl|1srl]], [[2ptk|2ptk]], [[1srm|1srm]], [[1f2f|1f2f]], [[1rlp|1rlp]], [[1nlp|1nlp]], [[1nlo|1nlo]]</td></tr>
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4agw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4agw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4agw RCSB], [http://www.ebi.ac.uk/pdbsum/4agw PDBsum]</span></td></tr>
<table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR, and EGFR, become resistant to adenosine triphosphate-competitive inhibitors through mutation of the so-called gatekeeper amino acid from a threonine to a large hydrophobic amino acid, such as an isoleucine or methionine. We have developed a new class of adenosine triphosphate competitive inhibitors, exemplified by HG-7-85-01, which is capable of inhibiting T315I- BCR-ABL (clinically observed in chronic myeloid leukemia), T670I-c-Kit (clinically observed in gastrointestinal stromal tumors), and T674I/M-PDGFRalpha (clinically observed in hypereosinophilic syndrome). HG-7-85-01 is unique among all currently reported kinase inhibitors in having the ability to accommodate either a gatekeeper threonine, present in the wild-type forms of these kinases, or a large hydrophobic amino acid without becoming a promiscuous kinase inhibitor. The distinctive ability of HG-7-85-01 to simultaneously inhibit both wild-type and mutant forms of several kinases of clinical relevance is an important step in the development of the next generation of tyrosine kinase inhibitors.


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Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants.,Weisberg E, Choi HG, Ray A, Barrett R, Zhang J, Sim T, Zhou W, Seeliger M, Cameron M, Azam M, Fletcher JA, Debiec-Rychter M, Mayeda M, Moreno D, Kung AL, Janne PA, Khosravi-Far R, Melo JV, Manley PW, Adamia S, Wu C, Gray N, Griffin JD Blood. 2010 May 27;115(21):4206-16. Epub 2010 Mar 18. PMID:20299508<ref>PMID:20299508</ref>
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{{STRUCTURE_4agw|  PDB=4agw  |  SCENE=  }}


===Discovery of a small molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases===
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>


 
==See Also==
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*[[Proto-oncogene tyrosine-protein kinase|Proto-oncogene tyrosine-protein kinase]]
The line below this paragraph, {{ABSTRACT_PUBMED_20299508}}, adds the Publication Abstract to the page
*[[Tyrosine kinase|Tyrosine kinase]]
(as it appears on PubMed at http://www.pubmed.gov), where 20299508 is the PubMed ID number.
== References ==
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<references/>
{{ABSTRACT_PUBMED_20299508}}
__TOC__
 
</StructureSection>
==About this Structure==
[[4agw]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AGW OCA].
 
==Reference==
<ref group="xtra">PMID:020299508</ref><references group="xtra"/>
[[Category: Gallus gallus]]
[[Category: Gallus gallus]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Non-specific protein-tyrosine kinase]]

Revision as of 08:30, 5 June 2014

Discovery of a small molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases

4agw, resolution 2.60Å

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