6typ: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 6typ is ~~ON HOLD until Paper~~ Publication

==KEAP1 Kelch domain in complex with Compound 2==

== Structural highlights ==

<table><tr><td colspan='2'>[[6typ]] 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=6TYP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6TYP FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=PKG:(3S)-3-[2-(benzenecarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-(1-ethyl-4-methyl-1H-benzotriazol-5-yl)propanoic+acid'>PKG</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=6typ FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6typ OCA], [http://pdbe.org/6typ PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6typ RCSB], [http://www.ebi.ac.uk/pdbsum/6typ PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6typ ProSAT]</span></td></tr>

</table>

== 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.

~~Authors:~~ Marcotte, D.J.

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>

~~Description~~: ~~KEAP1 Kelch domain in complex with Compound 2~~

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased~~ Structures]]

</div>

[[Category: Marcotte, D.J]]

== References ==

__TOC__

</StructureSection>

[[Category: Human]]

[[Category: Large Structures]]

[[Category: Marcotte, D J]]

[[Category: Keap1 kelch domain]]

[[Category: Peptide binding protein]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6typ is ON HOLD  until Paper Publication
+==KEAP1 Kelch domain in complex with Compound 2==
+<StructureSection load='6typ' size='340' side='right'caption='[[6typ]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6typ]] 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=6TYP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6TYP FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=PKG:(3S)-3-[2-(benzenecarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]-3-(1-ethyl-4-methyl-1H-benzotriazol-5-yl)propanoic+acid'>PKG</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=6typ FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6typ OCA], [http://pdbe.org/6typ PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6typ RCSB], [http://www.ebi.ac.uk/pdbsum/6typ PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6typ 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.
-Authors: Marcotte, D.J.
+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>
-Description: KEAP1 Kelch domain in complex with Compound 2
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Marcotte, D.J]]
+<div class="pdbe-citations 6typ" 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]]