5zxb
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of ACK1 with compound 10d== | |
| + | <StructureSection load='5zxb' size='340' side='right' caption='[[5zxb]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5zxb]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZXB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ZXB FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=9KO:N-{3-[7-{[6-(4-acetylpiperazin-1-yl)pyridin-3-yl]amino}-1-methyl-2-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl]-4-methylphenyl}-3-(trifluoromethyl)benzamide'>9KO</scene></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=5zxb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zxb OCA], [http://pdbe.org/5zxb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5zxb RCSB], [http://www.ebi.ac.uk/pdbsum/5zxb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5zxb ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/ACK1_HUMAN ACK1_HUMAN]] Non-receptor tyrosine-protein and serine/threonine-protein kinase that is implicated in cell spreading and migration, cell survival, cell growth and proliferation. Transduces extracellular signals to cytosolic and nuclear effectors. Phosphorylates AKT1, AR, MCF2, WASL and WWOX. Implicated in trafficking and clathrin-mediated endocytosis through binding to epidermal growth factor receptor (EGFR) and clathrin. Binds to both poly- and mono-ubiquitin and regulates ligand-induced degradation of EGFR, thereby contributing to the accumulation of EGFR at the limiting membrane of early endosomes. Downstream effector of CDC42 which mediates CDC42-dependent cell migration via phosphorylation of BCAR1. May be involved both in adult synaptic function and plasticity and in brain development. Activates AKT1 by phosphorylating it on 'Tyr-176'. Phosphorylates AR on 'Tyr-267' and 'Tyr-363' thereby promoting its recruitment to androgen-responsive enhancers (AREs). Phosphorylates WWOX on 'Tyr-287'. Phosphorylates MCF2, thereby enhancing its activity as a guanine nucleotide exchange factor (GEF) toward Rho family proteins. Contributes to the control of AXL receptor levels. Confers metastatic properties on cancer cells and promotes tumor growth by negatively regulating tumor suppressor such as WWOX and positively regulating pro-survival factors such as AKT1 and AR.<ref>PMID:10652228</ref> <ref>PMID:11278436</ref> <ref>PMID:16257963</ref> <ref>PMID:16247015</ref> <ref>PMID:17038317</ref> <ref>PMID:16472662</ref> <ref>PMID:18435854</ref> <ref>PMID:18262180</ref> <ref>PMID:19815557</ref> <ref>PMID:20383201</ref> <ref>PMID:20333297</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | GNF-7, a multitargeted kinase inhibitor, served as a dual kinase inhibitor of ACK1 and GCK, which provided a novel therapeutic strategy for overriding AML expressing NRAS mutation. This SAR study with GNF-7 derivatives, designed to target NRAS mutant-driven AML, led to identification of the extremely potent inhibitors, 10d, 10g, and 11i, which possess single-digit nanomolar inhibitory activity against both ACK1 and GCK. These substances strongly suppress proliferation of mutant NRAS expressing AML cells via apoptosis and AKT/mTOR signaling blockade. Compound 11i is superior to GNF-7 in terms of kinase inhibitory activity, cellular activity, and differential cytotoxicity. Moreover, 10k possessing a favorable mouse pharmacokinetic profile prolonged life-span of Ba/F3-NRAS-G12D injected mice and significantly delayed tumor growth of OCI-AML3 xenograft model without causing the prominent level of toxicity found with GNF-7. Taken together, this study provides insight into the design of novel ACK1 and GCK dual inhibitors for overriding NRAS mutant-driven AML. | ||
| - | + | First SAR Study for Overriding NRAS Mutant Driven Acute Myeloid Leukemia.,Cho H, Shin I, Ju E, Choi S, Hur W, Kim H, Hong E, Kim ND, Choi HG, Gray NS, Sim T J Med Chem. 2018 Sep 11. doi: 10.1021/acs.jmedchem.8b00882. PMID:30153003<ref>PMID:30153003</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5zxb" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Hong, E M]] | ||
| + | [[Category: Kim, H L]] | ||
| + | [[Category: Sim, T B]] | ||
| + | [[Category: Inhibitor]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 07:58, 26 September 2018
Crystal structure of ACK1 with compound 10d
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Categories: Hong, E M | Kim, H L | Sim, T B | Inhibitor | Kinase | Transferase
