6tym: Difference between revisions
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==KEAP1 Kelch domain in complex with Compound 9== | |||
<StructureSection load='6tym' size='340' side='right'caption='[[6tym]], [[Resolution|resolution]] 1.42Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6tym]] is a 1 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=6TYM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6TYM FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=08A:(3S)-3-[2-(benzenecarbonyl)-5-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-(1-ethyl-4-methyl-1H-benzotriazol-5-yl)propanoic+acid'>08A</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KEAP1, INRF2, KIAA0132, KLHL19 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6tym FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tym OCA], [http://pdbe.org/6tym PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6tym RCSB], [http://www.ebi.ac.uk/pdbsum/6tym PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6tym ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Nrf2 is a transcription factor regulating expression of the Phase II Antioxidant Response and plays an important role in neuroprotection and detoxification. Nrf2 activation is inhibited by interaction with Keap1. Covalent Keap1 inhibitors such as dimethyl fumarate (DMF) and RTA-408 are either on the market or in late stage clinical trials which implies potential benefit of Nrf2 activation. Activation of Nrf2 by disrupting Nrf2-Keap1 interaction through a non-covalent small molecule is an attractive approach with the promise of greater selectivity. However, there are no known non-covalent Nrf2 activators with acceptable pharmacokinetic properties to test the hypothesis in vivo. Based on our early reported work, using structural-based design, followed by extensive SAR exploration, we have identified a novel series of non-covalent Nrf2 activators, with sub-nanomolar binding affinity on Keap1 and single digit nanomolar activity in an astrocyte assay. A representative analog shows excellent oral PK and good Nrf2-dependent gene inductions in kidney. These results provide a peripheral in vivo tool compound to validate the biology of non-covalent activation of Nrf2. | |||
Design, synthesis and identification of novel, orally bioavailable non-covalent Nrf2 activators.,Ma B, Lucas B, Capacci A, Lin EY, Jones JH, Dechantsreiter M, Enyedy I, Marcotte D, Xiao G, Li B, Richter K Bioorg Med Chem Lett. 2020 Feb 15;30(4):126852. doi: 10.1016/j.bmcl.2019.126852. , Epub 2019 Dec 2. PMID:31898999<ref>PMID:31898999</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Marcotte, D | <div class="pdbe-citations 6tym" style="background-color:#fffaf0;"></div> | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Marcotte, D J]] | |||
[[Category: Keap1 kelch domain]] | |||
[[Category: Peptide binding protein]] | |||
Revision as of 12:07, 5 February 2020
KEAP1 Kelch domain in complex with Compound 9KEAP1 Kelch domain in complex with Compound 9
Structural highlights
Publication Abstract from PubMedNrf2 is a transcription factor regulating expression of the Phase II Antioxidant Response and plays an important role in neuroprotection and detoxification. Nrf2 activation is inhibited by interaction with Keap1. Covalent Keap1 inhibitors such as dimethyl fumarate (DMF) and RTA-408 are either on the market or in late stage clinical trials which implies potential benefit of Nrf2 activation. Activation of Nrf2 by disrupting Nrf2-Keap1 interaction through a non-covalent small molecule is an attractive approach with the promise of greater selectivity. However, there are no known non-covalent Nrf2 activators with acceptable pharmacokinetic properties to test the hypothesis in vivo. Based on our early reported work, using structural-based design, followed by extensive SAR exploration, we have identified a novel series of non-covalent Nrf2 activators, with sub-nanomolar binding affinity on Keap1 and single digit nanomolar activity in an astrocyte assay. A representative analog shows excellent oral PK and good Nrf2-dependent gene inductions in kidney. These results provide a peripheral in vivo tool compound to validate the biology of non-covalent activation of Nrf2. Design, synthesis and identification of novel, orally bioavailable non-covalent Nrf2 activators.,Ma B, Lucas B, Capacci A, Lin EY, Jones JH, Dechantsreiter M, Enyedy I, Marcotte D, Xiao G, Li B, Richter K Bioorg Med Chem Lett. 2020 Feb 15;30(4):126852. doi: 10.1016/j.bmcl.2019.126852. , Epub 2019 Dec 2. PMID:31898999[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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