6brf: Difference between revisions

<StructureSection load='6brf' size='340' side='right' caption='[[6brf]], [[Resolution|resolution]] 2.50&Aring;' scene=''>

<table><tr><td colspan='2'>[[6brf]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BRF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BRF FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=E44:2-chloro-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)pyrido[3,2-d]pyrimidine'>E44</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>

<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6br1|6br1]]</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=6brf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6brf OCA], [http://pdbe.org/6brf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6brf RCSB], [http://www.ebi.ac.uk/pdbsum/6brf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6brf ProSAT]</span></td></tr>

[[http://www.uniprot.org/uniprot/TBA1B_PIG TBA1B_PIG]] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. [[http://www.uniprot.org/uniprot/STMN4_HUMAN STMN4_HUMAN]] Exhibits microtubule-destabilizing activity. [[http://www.uniprot.org/uniprot/A0A287AGU7_PIG A0A287AGU7_PIG]] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain.[RuleBase:RU000352][SAAS:SAAS00031082]

We report the design, synthesis, and biological evaluation of heterocyclic-fused pyrimidines as tubulin polymerization inhibitors targeting the colchicine binding site with significantly improved therapeutic index. Additionally, for the first time, we report high-resolution X-ray crystal structures for the best compounds in this scaffold, 4a, 4b, 6a, and 8b. These structures not only confirm their direct binding to the colchicine site in tubulin and reveal their detailed molecular interactions but also contrast the previously published proposed binding mode. Compounds 4a and 6a significantly inhibited tumor growth in an A375 melanoma xenograft model and were accompanied by elevated levels of apoptosis and disruption of tumor vasculature. Finally, we demonstrated that compound 4a significantly overcame clinically relevant multidrug resistance in a paclitaxel resistant PC-3/TxR prostate cancer xenograft model. Collectively, these studies provide preclinical and structural proof of concept to support the continued development of this scaffold as a new generation of tubulin inhibitors.

Heterocyclic-Fused Pyrimidines as Novel Tubulin Polymerization Inhibitors Targeting the Colchicine Binding Site: Structural Basis and Antitumor Efficacy.,Banerjee S, Arnst KE, Wang Y, Kumar G, Deng S, Yang L, Li GB, Yang J, White SW, Li W, Miller DD J Med Chem. 2018 Feb 22;61(4):1704-1718. doi: 10.1021/acs.jmedchem.7b01858. Epub , 2018 Feb 12. PMID:29406710<ref>PMID:29406710</ref>

 

[[Category: Kumar, G]]

[[Category: Li, W]]

[[Category: Wang, Y]]

[[Category: White, S W]]

[[Category: Microtubule inhibitor]]