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==LTA4 hydrolase in complex with compound R(13)== | ==LTA4 hydrolase in complex with compound R(13)== | ||
<StructureSection load='7av0' size='340' side='right'caption='[[7av0]]' scene=''> | <StructureSection load='7av0' size='340' side='right'caption='[[7av0]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AV0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AV0 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7av0]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AV0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AV0 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7av0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7av0 OCA], [https://pdbe.org/7av0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7av0 RCSB], [https://www.ebi.ac.uk/pdbsum/7av0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7av0 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=RZB:(3~{R})-3-azanyl-4-[5-[4-(4-chloranylphenoxy)phenyl]-1,2,3,4-tetrazol-2-yl]butanoic+acid'>RZB</scene>, <scene name='pdbligand=YB:YTTERBIUM+(III)+ION'>YB</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Leukotriene-A(4)_hydrolase Leukotriene-A(4) hydrolase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.3.2.6 3.3.2.6] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7av0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7av0 OCA], [https://pdbe.org/7av0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7av0 RCSB], [https://www.ebi.ac.uk/pdbsum/7av0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7av0 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/LKHA4_HUMAN LKHA4_HUMAN]] Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity.<ref>PMID:1897988</ref> <ref>PMID:1975494</ref> <ref>PMID:2244921</ref> <ref>PMID:12207002</ref> <ref>PMID:11917124</ref> <ref>PMID:15078870</ref> <ref>PMID:18804029</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The cytosolic metalloenzyme leukotriene A4 hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B4 (LTB4). Preclinical studies have validated this enzyme as an attractive drug target in chronic inflammatory diseases. Despite several attempts, no LTA4H inhibitor has reached the market, yet. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A focused fragment screen identified hits that could be cocrystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006, a picomolar LTA4H inhibitor with exquisite whole blood potency and long-lasting pharmacodynamic effects. Due to its high selectivity and its ability to fully suppress LTB4 generation at low exposures in vivo, LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently investigated in phase II clinical trials in inflammatory acne, hidradenitis suppurativa, ulcerative colitis, and NASH. | |||
Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A4 Hydrolase.,Markert C, Thoma G, Srinivas H, Bollbuck B, Luond RM, Miltz W, Walchli R, Wolf R, Hinrichs J, Bergsdorf C, Azzaoui K, Penno CA, Klein K, Wack N, Jager P, Hasler F, Beerli C, Loetscher P, Dawson J, Wieczorek G, Numao S, Littlewood-Evans A, Rohn TA J Med Chem. 2021 Feb 25;64(4):1889-1903. doi: 10.1021/acs.jmedchem.0c01955. Epub , 2021 Feb 16. PMID:33592148<ref>PMID:33592148</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7av0" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Srinivas H]] | [[Category: Srinivas, H]] | ||
[[Category: Complex]] | |||
[[Category: Hydrolase]] | |||
[[Category: Inhibitor]] | |||
Revision as of 20:54, 10 March 2021
LTA4 hydrolase in complex with compound R(13)LTA4 hydrolase in complex with compound R(13)
Structural highlights
Function[LKHA4_HUMAN] Epoxide hydrolase that catalyzes the final step in the biosynthesis of the proinflammatory mediator leukotriene B4. Has also aminopeptidase activity.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedThe cytosolic metalloenzyme leukotriene A4 hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B4 (LTB4). Preclinical studies have validated this enzyme as an attractive drug target in chronic inflammatory diseases. Despite several attempts, no LTA4H inhibitor has reached the market, yet. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A focused fragment screen identified hits that could be cocrystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006, a picomolar LTA4H inhibitor with exquisite whole blood potency and long-lasting pharmacodynamic effects. Due to its high selectivity and its ability to fully suppress LTB4 generation at low exposures in vivo, LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently investigated in phase II clinical trials in inflammatory acne, hidradenitis suppurativa, ulcerative colitis, and NASH. Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A4 Hydrolase.,Markert C, Thoma G, Srinivas H, Bollbuck B, Luond RM, Miltz W, Walchli R, Wolf R, Hinrichs J, Bergsdorf C, Azzaoui K, Penno CA, Klein K, Wack N, Jager P, Hasler F, Beerli C, Loetscher P, Dawson J, Wieczorek G, Numao S, Littlewood-Evans A, Rohn TA J Med Chem. 2021 Feb 25;64(4):1889-1903. doi: 10.1021/acs.jmedchem.0c01955. Epub , 2021 Feb 16. PMID:33592148[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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