Therapeutic Targets Database
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TTD Target ID: TTDC00068

Target Information
NameCathepsin K    
Type of targetClinical trial target    
SynonymsCathepsin O    
Cathepsin O2    
Cathepsin X    
DiseaseBone Metastases
[ICD9: 198.5   ICD10: C79.51]
[1][2][3]
Cancer, unspecific
[ICD9: 140-229   ICD10: C00-C96]
[4]
Osteoporosis
[ICD9: 733.0   ICD10: M80-M81]
[1][2][3]
Postmenopausal Women with Osteoporosis
[ICD9: 733.0   ICD10: M80-M81]
[5][6][7]
Rheumatoid arthritis
[ICD9: 714   ICD10: M05-M06]
[8]
Drug(s)MK-0822Phase IIIOstereoporosis[9][10]
OdanacatibPhase IIIPostmenopausal Women with Osteoporosis[5][6][7]
SAR114137Phase IOsteoarthritic pain
BalicatibDiscontinued in Phase IIOsteoporosis[11]
MIV-701Discontinued in Phase I/IIOsteoporosis[12]
RelacatibSuspend in Phase I in GSK 2005 ReprotOsteoporosis[1][2][3]
RelacatibSuspend in Phase II in GSK 2005 ReprotBone Metastases[1][2][3]
BioChemical ClassHydrolases acting on peptide bonds (Peptidases)    
EC NumberEC 3.4.22.38
PathwayLysosome
UniProt IDP43235
PDB Structure1ATK; 1AU0; 1AU2; 1AU3; 1AU4; 1AYU; 1AYV; 1AYW; 1BGO; 1BY8; 1MEM; 1NL6; 1NLJ; 1Q6K; 1SNK; 1TU6; 1U9V; 1U9W; 1U9X; 1VSN; 1YK7; 1YK8; 1YT7; 2ATO; 2AUX; 2AUZ; 2BDL; 2R6N; 3C9E; 3H7D; 3KW9; 3KWB; 3KWZ; 3KX1; 3O0U; 3O1G; 3OVZ; 4DMX; 4DMY; 7PCK.    
FunctionClosely 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.    
SequenceMWGLKVLLLPVVSFALYPEEILDTHWELWKKTHRKQYNNKVDEISRRLIWEKNLKYISIH NLEASLGVHTYELAMNHLGDMTSEEVVQKMTGLKVPLSHSRSNDTLYIPEWEGRAPDSVD YRKKGYVTPVKNQGQCGSCWAFSSVGALEGQLKKKTGKLLNLSPQNLVDCVSENDGCGGG YMTNAFQYVQKNRGIDSEDAYPYVGQEESCMYNPTGKAAKCRGYREIPEGNEKALKRAVA RVGPVSVAIDASLTSFQFYSKGVYYDESCNSDNLNHAVLAVGYGIQKGNKHWIIKNSWGE NWGNKGYILMARNKNNACGIANLASFPKM
Related US Patent6,284,777
6,313,119
6,331,542
6,420,364
6,455,502
6,462,076
6,476,026
6,492,362
6,506,733
6,518,267
6,525,036
6,525,052
6,534,498
6,562,842
6,566,373
6,576,630
6,583,137
6,586,466
6,593,327
6,596,715
6,608,057
6,635,621
6,642,239
6,649,642
Target ValidationClick to Find Target Validation Information.    
Inhibitor (S)-1-benzylcyclopentyl 1-oxohexan-2-ylcarbamate[13]
(S)-tert-butyl 1-oxohexan-2-ylcarbamate[13]
(S)-tert-butyl 4-methyl-1-oxopentan-2-ylcarbamate[13]
2-cyclohexylamino-pyridine-2-carbonitrile[14]
2-cyclohexylamino-pyrimidine-4-carbonitrile[14]
3-Amino-5-Phenylpentane[15]
4-cycloheptyl-6-propylpyrimidine-2-carbonitrile[16]
4-cyclohexyl-6-propylpyrimidine-2-carbonitrile[16]
4-cyclohexylamino-pyrimidine-2-carbonitrile[14]
4-cyclooctyl-6-propylpyrimidine-2-carbonitrile[16]
4-phenyl-6-propylpyrimidine-2-carbonitrile[17]
4-propyl-6-m-tolylpyrimidine-2-carbonitrile[17]
BOCEPREVIR[18]
Balicatib[11]
Boc-Agly-Val-Agly-OEt[19]
GNF-PF-5434[20]
L-006235-1[21]
L-873724[1]
MIV-701[12]
MK-0822[9][10]
MK-1256[22]
N- (1-[23]
N- (4-phenylbenzoyl)-phenylalanyl-glycine-nitrile[24]
N- (benzyloxycarbonyl)-leucyl-glycine-nitrile[24]
N- (cyanomethyl)cyclohex-1-ene-1-carboxamide[23]
N- (tert-butoxycarbonyl)-isoleucyl-glycine-nitrile[24]
N- (tert-butoxycarbonyl)-leucyl-glycine-nitrile[24]
N- (tert-butoxycarbonyl)-methionyl-glycine-nitrile[24]
N- (tert-butoxycarbonyl)-norleucyl-glycine-nitrile[24]
N- (tert-butoxycarbonyl)-norvalyl-glycine-nitrile[24]
N- (tert-butoxycarbonyl)-valyl-glycine-nitrile[24]
N-acetyl-phenylalanyl-glycine-nitrile[24]
N-benzoyl-phenylalanyl-glycine-nitrile[24]
Odanacatib[5][6][7]
P2,P3 Ketoamide derivative[25]
Peptide aldehydes[8]
Pyrrolidine-1-carbonitrile[26]
Relacatib[1][2][3]
TERT-BUTYL 2-CYANO-2-METHYLHYDRAZINECARBOXYLATE[27]
Tert-Butyl (1s)-1-Cyclohexyl-2-Oxoethylcarbamate[27]
Z-Ala-Leu-His-Agly-Ile-Val-OMe[19]
Z-Ala-Leu-Nal-Agly-Ile-Val-OMe[19]
Z-Ala-Leu-Phe-Agly-Ile-Val-OMe[19]
Z-Ala-Leu-Tyr (Me)-Agly-Ile-Val-OMe[19]
Z-Ala-Leu-lle-Agly-Ile-Val-NHBzl[19]
Z-Ala-Leu-lle-Agly-Ile-Val-OMe[19]
Z-Arg-Leu-Val-Agly-Ala-Gly-NH2[19]
Z-Arg-Leu-Val-Agly-Ile-Val-Trp-NH2[19]
Z-Arg-Leu-Val-Agly-Ileu-Val-OMe[19]
Z-Arg-Leu-Val-Agly-Trp-Val-Ala-NH2[19]
Z-Arg-Leu-Val-Agly-Val-Ala-NH2[19]
Z-leu-Val-Agly-Val-OBzl[19]
tert-butyl (2S)-1-cyanopyrrolidine-2-carboxylate[26]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Bioorg Med Chem Lett. 2008 Feb 1;18(3):923-8. Epub 2008 Jan 15.The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. To Reference
Ref 2A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys. Bone. 2007 Jan;40(1):122-31. Epub 2006 Sep 7. To Reference
Ref 3Structure activity relationships of 5-, 6-, and 7-methyl-substituted azepan-3-one cathepsin K inhibitors. J Med Chem. 2006 Mar 9;49(5):1597-612. To Reference
Ref 4The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res. 1997 Dec 1;57(23):5386-90. To Reference
Ref 5Future therapeutic targets in osteoporosis. Curr Opin Rheumatol. 2009 Jul;21(4):380-5. To Reference
Ref 6Biol Chem. 2009 Sep;390(9):941-8.Pharmacological inhibitors to identify roles of cathepsin K in cell-based studies: a comparison of available tools. To Reference
Ref 7Effect of the cathepsin K inhibitor odanacatib on bone resorption biomarkers in healthy postmenopausal women: two double-blind, randomized, placebo-controlled phase I studies. Clin Pharmacol Ther. 2009 Aug;86(2):175-82. Epub 2009 May 6. To Reference
Ref 8Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo. J Bone Miner Res. 1997 Sep;12(9):1396-406. To Reference
Ref 9Merck. Product Development Pipeline. July 15 2009. To Reference
Ref 10Clin Pharmacol Ther. 2008 Jan;83(1):172-6. Epub 2007 Dec 12.Cathepsin K inhibitors: a novel target for osteoporosis therapy. To Reference
Ref 11Current and future treatments of bone metastases. Expert Opin Emerg Drugs. 2008 Dec;13(4):609-27. To Reference
Ref 12Medivir Begins Initial Clinical Trial of Osteoporosis Drug Cathepsin K Inhibitor. Medivir. 2007 To Reference
Ref 13Bioorg Med Chem Lett. 2006 Feb 15;16(4):978-83. Epub 2005 Nov 15.Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors? To Reference
Ref 14J Med Chem. 2007 Feb 22;50(4):591-4. Epub 2007 Jan 27.2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K. To Reference
Ref 15Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. To Reference
Ref 16Bioorg Med Chem Lett. 2010 Mar 1;20(5):1524-7. Epub 2010 Jan 25.Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors. To Reference
Ref 17Bioorg Med Chem Lett. 2010 Aug 1;20(15):4447-50. Epub 2010 Jun 15.2-Phenyl-9H-purine-6-carbonitrile derivatives as selective cathepsin S inhibitors. To Reference
Ref 18Antimicrob Agents Chemother. 2010 Jan;54(1):305-11. Epub 2009 Oct 19.MK-7009, a potent and selective inhibitor of hepatitis C virus NS3/4A protease. To Reference
Ref 19J Med Chem. 2002 Sep 12;45(19):4202-11.Azapeptides structurally based upon inhibitory sites of cystatins as potent and selective inhibitors of cysteine proteases. To Reference
Ref 20Bioorg Med Chem. 2009 Feb 1;17(3):1064-70. Epub 2008 Feb 7.Substrate optimization for monitoring cathepsin C activity in live cells. To Reference
Ref 21J Med Chem. 2005 Dec 1;48(24):7535-43.Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. To Reference
Ref 22J Med Chem. 2008 Oct 23;51(20):6410-20. Epub 2008 Sep 24.Identification of a nonbasic, nitrile-containing cathepsin K inhibitor (MK-1256) that is efficacious in a monkey model of osteoporosis. To Reference
Ref 23J Med Chem. 2006 Feb 9;49(3):1066-79.Beta-substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K. To Reference
Ref 24J Med Chem. 2005 Dec 1;48(24):7688-707.Interaction of papain-like cysteine proteases with dipeptide-derived nitriles. To Reference
Ref 25Bioorg Med Chem Lett. 2004 Oct 4;14(19):4897-902.Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1', P1, and/or P3 substitutions. To Reference
Ref 26Bioorg Med Chem Lett. 2005 Jun 15;15(12):3039-43.Acyclic cyanamide-based inhibitors of cathepsin K. To Reference
Ref 27Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. To Reference



 

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