5uvc: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Design, Synthesis, and Evaluation of the First Selective and Potent G-protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure== | |||
<StructureSection load='5uvc' size='340' side='right' caption='[[5uvc]], [[Resolution|resolution]] 2.65Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5uvc]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UVC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UVC FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8PV:N-benzyl-3-({[5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]methyl}amino)benzamide'>8PV</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5uuu|5uuu]]</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Beta-adrenergic-receptor]_kinase [Beta-adrenergic-receptor] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.15 2.7.11.15] </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=5uvc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uvc OCA], [http://pdbe.org/5uvc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uvc RCSB], [http://www.ebi.ac.uk/pdbsum/5uvc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uvc ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/ARBK1_HUMAN ARBK1_HUMAN]] Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner.<ref>PMID:19306925</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of beta-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC50 = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates beta-adrenergic receptor (betaAR)-mediated cAMP accumulation and prevents internalization of betaARs in beta2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment. | |||
Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure.,Okawa T, Aramaki Y, Yamamoto M, Kobayashi T, Fukumoto S, Toyoda Y, Henta T, Hata A, Ikeda S, Kaneko M, Hoffman ID, Sang BC, Zou H, Kawamoto T J Med Chem. 2017 Aug 24;60(16):6942-6990. doi: 10.1021/acs.jmedchem.7b00443. Epub, 2017 Aug 3. PMID:28699740<ref>PMID:28699740</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Lawson, J | <div class="pdbe-citations 5uvc" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Hoffman, I D]] | |||
[[Category: Lawson, J D]] | |||
[[Category: Heart failure]] | |||
[[Category: Inhibitor]] | |||
[[Category: Kinase]] | |||
[[Category: Transferase-transferase inhibitor complex]] | |||
Revision as of 06:49, 6 September 2017
Design, Synthesis, and Evaluation of the First Selective and Potent G-protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart FailureDesign, Synthesis, and Evaluation of the First Selective and Potent G-protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure
Structural highlights
Function[ARBK1_HUMAN] Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner.[1] Publication Abstract from PubMedA novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of beta-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC50 = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates beta-adrenergic receptor (betaAR)-mediated cAMP accumulation and prevents internalization of betaARs in beta2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment. Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure.,Okawa T, Aramaki Y, Yamamoto M, Kobayashi T, Fukumoto S, Toyoda Y, Henta T, Hata A, Ikeda S, Kaneko M, Hoffman ID, Sang BC, Zou H, Kawamoto T J Med Chem. 2017 Aug 24;60(16):6942-6990. doi: 10.1021/acs.jmedchem.7b00443. Epub, 2017 Aug 3. PMID:28699740[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||||