7n4n: Difference between revisions
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==== | ==BACE-2 in complex with ligand 36== | ||
<StructureSection load='7n4n' size='340' side='right'caption='[[7n4n]]' scene=''> | <StructureSection load='7n4n' size='340' side='right'caption='[[7n4n]], [[Resolution|resolution]] 1.41Å' 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= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7n4n]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7N4N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N4N 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=7n4n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n4n OCA], [https://pdbe.org/7n4n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n4n RCSB], [https://www.ebi.ac.uk/pdbsum/7n4n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n4n ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.41Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0BK:~{N}-[3-[(2~{S},5~{R})-6-azanyl-2-(fluoranylmethyl)-5-methyl-5-methylsulfonyl-3,4-dihydropyridin-2-yl]-4-fluoranyl-phenyl]-6-methoxy-pyrimidine-4-carboxamide'>0BK</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene></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=7n4n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n4n OCA], [https://pdbe.org/7n4n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n4n RCSB], [https://www.ebi.ac.uk/pdbsum/7n4n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n4n ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/BACE2_HUMAN BACE2_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. It has also been shown that it can cleave APP between residues 671 and 672.<ref>PMID:10591213</ref> <ref>PMID:11083922</ref> <ref>PMID:15857888</ref> <ref>PMID:11423558</ref> <ref>PMID:16816112</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pKa and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 (12), which gave robust dose-dependent BACE1-mediated amyloid beta lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that 12 has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, 12 was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future. | |||
JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate.,Rombouts FJR, Kusakabe KI, Alexander R, Austin N, Borghys H, De Cleyn M, Dhuyvetter D, Gijsen HJM, Hrupka B, Jacobs T, Jerhaoui S, Lammens L, Leclercq L, Tsubone K, Ueno T, Morimoto K, Einaru S, Sumiyoshi H, Van den Bergh A, Vos A, Surkyn M, Teisman A, Moechars D J Med Chem. 2021 Sep 23. doi: 10.1021/acs.jmedchem.1c00935. PMID:34553934<ref>PMID:34553934</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7n4n" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Beta secretase 3D structures|Beta secretase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Shaffer PL]] | ||
Latest revision as of 09:35, 21 November 2024
BACE-2 in complex with ligand 36BACE-2 in complex with ligand 36
Structural highlights
FunctionBACE2_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. It has also been shown that it can cleave APP between residues 671 and 672.[1] [2] [3] [4] [5] Publication Abstract from PubMedThe discovery of a novel 2-aminotetrahydropyridine class of BACE1 inhibitors is described. Their pKa and lipophilicity were modulated by a pending sulfonyl group, while good permeability and brain penetration were achieved via intramolecular hydrogen bonding. BACE1 selectivity over BACE2 was achieved in the S3 pocket by a novel bicyclic ring system. An optimization addressing reactive metabolite formation, cardiovascular safety, and CNS toxicity is described, leading to the clinical candidate JNJ-67569762 (12), which gave robust dose-dependent BACE1-mediated amyloid beta lowering without showing BACE2-dependent hair depigmentation in preclinical models. We show that 12 has a favorable projected human dose and PK and hence presented us with an opportunity to test a highly selective BACE1 inhibitor in humans. However, 12 was found to have a QT effect upon repeat dosing in dogs and its development was halted in favor of other selective leads, which will be reported in the future. JNJ-67569762, A 2-Aminotetrahydropyridine-Based Selective BACE1 Inhibitor Targeting the S3 Pocket: From Discovery to Clinical Candidate.,Rombouts FJR, Kusakabe KI, Alexander R, Austin N, Borghys H, De Cleyn M, Dhuyvetter D, Gijsen HJM, Hrupka B, Jacobs T, Jerhaoui S, Lammens L, Leclercq L, Tsubone K, Ueno T, Morimoto K, Einaru S, Sumiyoshi H, Van den Bergh A, Vos A, Surkyn M, Teisman A, Moechars D J Med Chem. 2021 Sep 23. doi: 10.1021/acs.jmedchem.1c00935. PMID:34553934[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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