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| | ==Cathepsin K inhibitor== | | ==Cathepsin K inhibitor== |
| - | <StructureSection load='4dmx' size='340' side='right' caption='[[4dmx]], [[Resolution|resolution]] 1.70Å' scene=''> | + | <StructureSection load='4dmx' size='340' side='right'caption='[[4dmx]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4dmx]] 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=4DMX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DMX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4dmx]] is a 1 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=4DMX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DMX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0LB:(1R,2R)-N-(1-CYANOCYCLOPROPYL)-2-{[4-(4-FLUOROPHENYL)PIPERAZIN-1-YL]CARBONYL}CYCLOHEXANECARBOXAMIDE'>0LB</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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]] 1.7Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4dmy|4dmy]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0LB:(1R,2R)-N-(1-CYANOCYCLOPROPYL)-2-{[4-(4-FLUOROPHENYL)PIPERAZIN-1-YL]CARBONYL}CYCLOHEXANECARBOXAMIDE'>0LB</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CTSK, CTSO, CTSO2 ([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'>[https://proteopedia.org/fgij/fg.htm?mol=4dmx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dmx OCA], [https://pdbe.org/4dmx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dmx RCSB], [https://www.ebi.ac.uk/pdbsum/4dmx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dmx ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cathepsin_K Cathepsin K], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.38 3.4.22.38] </span></td></tr>
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| - | <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=4dmx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dmx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dmx RCSB], [http://www.ebi.ac.uk/pdbsum/4dmx PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN]] Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:[http://omim.org/entry/265800 265800]]. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.<ref>PMID:8703060</ref> <ref>PMID:9529353</ref> <ref>PMID:10491211</ref> <ref>PMID:10878663</ref> | + | [https://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN] Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:[https://omim.org/entry/265800 265800]. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.<ref>PMID:8703060</ref> <ref>PMID:9529353</ref> <ref>PMID:10491211</ref> <ref>PMID:10878663</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN]] Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. | + | [https://www.uniprot.org/uniprot/CATK_HUMAN CATK_HUMAN] Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4dmx" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Cathepsin|Cathepsin]] | + | *[[Cathepsin 3D structures|Cathepsin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Cathepsin K]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Beeley, H]] | + | [[Category: Beeley H]] |
| - | [[Category: Bowyer, J]] | + | [[Category: Bowyer J]] |
| - | [[Category: Cook, C R]] | + | [[Category: Cook CR]] |
| - | [[Category: Crawford, J J]] | + | [[Category: Crawford JJ]] |
| - | [[Category: Dossetter, A G]] | + | [[Category: Dossetter AG]] |
| - | [[Category: Finlayson, J E]] | + | [[Category: Finlayson JE]] |
| - | [[Category: Gutierrez, P M]] | + | [[Category: Gutierrez PM]] |
| - | [[Category: Heron, N M]] | + | [[Category: Heron NM]] |
| - | [[Category: Heyes, C]] | + | [[Category: Heyes C]] |
| - | [[Category: Highton, A J]] | + | [[Category: Highton AJ]] |
| - | [[Category: Hudson, J A]] | + | [[Category: Hudson JA]] |
| - | [[Category: Jestel, A]] | + | [[Category: Jestel A]] |
| - | [[Category: Kenny, P W]] | + | [[Category: Kenny PW]] |
| - | [[Category: Krapp, S]] | + | [[Category: Krapp S]] |
| - | [[Category: MacFaul, P A]] | + | [[Category: MacFaul PA]] |
| - | [[Category: Martin, S]] | + | [[Category: Martin S]] |
| - | [[Category: McGuire, T M]] | + | [[Category: McGuire TM]] |
| - | [[Category: Morley, A D]] | + | [[Category: Morley AD]] |
| - | [[Category: Morris, J J]] | + | [[Category: Morris JJ]] |
| - | [[Category: Page, K M]] | + | [[Category: Page KM]] |
| - | [[Category: Ribeiro, L Rosenbrier]] | + | [[Category: Rosenbrier Ribeiro L]] |
| - | [[Category: Sawney, H]] | + | [[Category: Sawney H]] |
| - | [[Category: Smith, C]] | + | [[Category: Smith C]] |
| - | [[Category: Steinbacher, S]] | + | [[Category: Steinbacher S]] |
| - | [[Category: Vickers, M]] | + | [[Category: Vickers M]] |
| - | [[Category: Cathepsin k inhibitor]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Osteoarthritis]]
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| Structural highlights
Disease
CATK_HUMAN Defects in CTSK are the cause of pycnodysostosis (PKND) [MIM:265800. PKND is an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature.[1] [2] [3] [4]
Function
CATK_HUMAN Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling. Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation.
Publication Abstract from PubMed
Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in-vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis based design using existing structural information. Optimisation using small substituents, knowledge from matched molecular pairs and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
(1R,2R)-N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole -2-carbonyl)cyclohexanecarboxamide (AZD4996): A potent and highly selective Cathepsin K inhibitor for the treatment of osteoarthritis.,Dossetter A, Beeley H, Bowyer J, Cook CR, Crawford JJ, Finlayson JE, Heron NM, Heyes C, Highton AJ, Hudson JA, Jestel A, Kenny PW, Krapp S, Martin S, Macfaul PA, McGuire TM, Morentin-Gutierrez P, Morley AD, Morris JJ, Page KM, Rosenbrier-Ribeiro L, Sawney H, Steinbacher S, Smith C, Vickers M J Med Chem. 2012 Jun 28. PMID:22742641[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 1996 Aug 30;273(5279):1236-8. PMID:8703060
- ↑ Gelb BD, Willner JP, Dunn TM, Kardon NB, Verloes A, Poncin J, Desnick RJ. Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. Am J Hum Genet. 1998 Apr;62(4):848-54. PMID:9529353 doi:S0002-9297(07)60977-X
- ↑ Ho N, Punturieri A, Wilkin D, Szabo J, Johnson M, Whaley J, Davis J, Clark A, Weiss S, Francomano C. Mutations of CTSK result in pycnodysostosis via a reduction in cathepsin K protein. J Bone Miner Res. 1999 Oct;14(10):1649-53. PMID:10491211
- ↑ Haagerup A, Hertz JM, Christensen MF, Binderup H, Kruse TA. Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population. Eur J Hum Genet. 2000 Jun;8(6):431-6. PMID:10878663 doi:10.1038/sj.ejhg.5200481
- ↑ Dossetter A, Beeley H, Bowyer J, Cook CR, Crawford JJ, Finlayson JE, Heron NM, Heyes C, Highton AJ, Hudson JA, Jestel A, Kenny PW, Krapp S, Martin S, Macfaul PA, McGuire TM, Morentin-Gutierrez P, Morley AD, Morris JJ, Page KM, Rosenbrier-Ribeiro L, Sawney H, Steinbacher S, Smith C, Vickers M. (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole -2-carbonyl)cyclohexanecarboxamide (AZD4996): A potent and highly selective Cathepsin K inhibitor for the treatment of osteoarthritis. J Med Chem. 2012 Jun 28. PMID:22742641 doi:10.1021/jm3007257
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