4dmx: Difference between revisions

Revision as of 23:13, 11 August 2016

Cathepsin K inhibitorCathepsin K inhibitor

Structural highlights

4dmx is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	4dmy
Gene:	CTSK, CTSO, CTSO2 (HUMAN)
Activity:	Cathepsin K, with EC number 3.4.22.38
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

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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OCA

[1] 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

[2] 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

[3] 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

[4] 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

[5] 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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@@ Line 1: / Line 1: @@
 ==Cathepsin K inhibitor==
 <StructureSection load='4dmx' size='340' side='right' caption='[[4dmx]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
@@ Line 7: / Line 8: @@
 <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='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>
-<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>
+<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://pdbe.org/4dmx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dmx RCSB], [http://www.ebi.ac.uk/pdbsum/4dmx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dmx ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 22: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4dmx" style="background-color:#fffaf0;"></div>
 ==See Also==

4dmx: Difference between revisions

Revision as of 23:13, 11 August 2016

Cathepsin K inhibitorCathepsin K inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

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4dmx: Difference between revisions

Revision as of 23:13, 11 August 2016

Cathepsin K inhibitorCathepsin K inhibitor

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

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