Target Information

Target General Infomation
Target ID
T11388
Former ID
TTDC00068
Target Name
Cathepsin K
Gene Name
CTSK
Synonyms
Cathepsin O; Cathepsin O2; Cathepsin X; CTSK
Target Type
Clinical Trial
Disease Asthma [ICD10: J45]
Bone disease [ICD10: M00-M99]
Bone metastases [ICD9: 198.5; ICD10: C79.51]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Osteopenia [ICD9: 733.9; ICD10: M85.8]
Ostereoporosis [ICD9: 733; ICD10: M80-M81]
Osteoporosis [ICD9: 733.0, V07.4; ICD10: M80-M81, Z79.890]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06]
Function
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.
BioChemical Class
Peptidase
Target Validation
T11388
UniProt ID
P43235
EC Number
EC 3.4.22.38
Sequence
MWGLKVLLLPVVSFALYPEEILDTHWELWKKTHRKQYNNKVDEISRRLIWEKNLKYISIH
NLEASLGVHTYELAMNHLGDMTSEEVVQKMTGLKVPLSHSRSNDTLYIPEWEGRAPDSVD
YRKKGYVTPVKNQGQCGSCWAFSSVGALEGQLKKKTGKLLNLSPQNLVDCVSENDGCGGG
YMTNAFQYVQKNRGIDSEDAYPYVGQEESCMYNPTGKAAKCRGYREIPEGNEKALKRAVA
RVGPVSVAIDASLTSFQFYSKGVYYDESCNSDNLNHAVLAVGYGIQKGNKHWIIKNSWGE
NWGNKGYILMARNKNNACGIANLASFPKM
Drugs and Mode of Action
Drug(s) Odanacatib Drug Info Phase 1 Ostereoporosis [1]
SAR-114137 Drug Info Phase 1 Pain [2]
VEL-0230 Drug Info Phase 1 Rheumatoid arthritis [3]
Balicatib Drug Info Discontinued in Phase 2 Osteoporosis [4], [5]
ONO-5334 Drug Info Discontinued in Phase 2 Osteopenia [6]
Relacatib Drug Info Discontinued in Phase 2 Bone metastases [4], [7]
MIV-701 Drug Info Discontinued in Phase 1 Osteoporosis [8]
Relacatib Drug Info Discontinued in Phase 1 Osteoporosis [4], [7]
Inhibitor (S)-1-benzylcyclopentyl 1-oxohexan-2-ylcarbamate Drug Info [9]
(S)-tert-butyl 1-oxohexan-2-ylcarbamate Drug Info [9]
(S)-tert-butyl 4-methyl-1-oxopentan-2-ylcarbamate Drug Info [9]
2-cyclohexylamino-pyridine-2-carbonitrile Drug Info [10]
2-cyclohexylamino-pyrimidine-4-carbonitrile Drug Info [10]
3-Amino-5-Phenylpentane Drug Info [11]
4-cycloheptyl-6-propylpyrimidine-2-carbonitrile Drug Info [12]
4-cyclohexyl-6-propylpyrimidine-2-carbonitrile Drug Info [12]
4-cyclohexylamino-pyrimidine-2-carbonitrile Drug Info [10]
4-cyclooctyl-6-propylpyrimidine-2-carbonitrile Drug Info [12]
4-phenyl-6-propylpyrimidine-2-carbonitrile Drug Info [13]
4-propyl-6-m-tolylpyrimidine-2-carbonitrile Drug Info [13]
AM-3701 Drug Info [14]
Balicatib Drug Info [4]
BF/PC-21 Drug Info [14]
Boc-Agly-Val-Agly-OEt Drug Info [15]
compound 1b Drug Info [9]
GNF-PF-5434 Drug Info [16]
GW-2592X Drug Info [14]
L-006235-1 Drug Info [17]
L-873724 Drug Info [18]
MIV-701 Drug Info [19]
N-(1-((cyanomethyl)carbamoyl)cyclohexyl)benzamide Drug Info [20]
N-(4-phenylbenzoyl)-phenylalanyl-glycine-nitrile Drug Info [21]
N-(benzyloxycarbonyl)-leucyl-glycine-nitrile Drug Info [21]
N-(cyanomethyl)cyclohex-1-ene-1-carboxamide Drug Info [20]
N-(tert-butoxycarbonyl)-isoleucyl-glycine-nitrile Drug Info [21]
N-(tert-butoxycarbonyl)-leucyl-glycine-nitrile Drug Info [21]
N-(tert-butoxycarbonyl)-methionyl-glycine-nitrile Drug Info [21]
N-(tert-butoxycarbonyl)-norleucyl-glycine-nitrile Drug Info [21]
N-(tert-butoxycarbonyl)-norvalyl-glycine-nitrile Drug Info [21]
N-(tert-butoxycarbonyl)-valyl-glycine-nitrile Drug Info [21]
N-acetyl-phenylalanyl-glycine-nitrile Drug Info [21]
N-benzoyl-phenylalanyl-glycine-nitrile Drug Info [21]
Odanacatib Drug Info [22], [23]
ONO-5334 Drug Info [24], [25]
P2,P3 Ketoamide derivative Drug Info [26]
Peptide aldehydes Drug Info [27]
Pyrrolidine-1-carbonitrile Drug Info [28]
Relacatib Drug Info [29], [30], [18]
SAR-114137 Drug Info [2]
Tert-butyl (2S)-1-cyanopyrrolidine-2-carboxylate Drug Info [28]
TERT-BUTYL 2-CYANO-2-METHYLHYDRAZINECARBOXYLATE Drug Info [31]
Tert-Butyl(1s)-1-Cyclohexyl-2-Oxoethylcarbamate Drug Info [31]
VEL-0230 Drug Info [32]
Z-Ala-Leu-His-Agly-Ile-Val-OMe Drug Info [15]
Z-Ala-Leu-lle-Agly-Ile-Val-NHBzl Drug Info [15]
Z-Ala-Leu-lle-Agly-Ile-Val-OMe Drug Info [15]
Z-Ala-Leu-Nal-Agly-Ile-Val-OMe Drug Info [15]
Z-Ala-Leu-Phe-Agly-Ile-Val-OMe Drug Info [15]
Z-Ala-Leu-Tyr(Me)-Agly-Ile-Val-OMe Drug Info [15]
Z-Arg-Leu-Val-Agly-Ala-Gly-NH2 Drug Info [15]
Z-Arg-Leu-Val-Agly-Ile-Val-Trp-NH2 Drug Info [15]
Z-Arg-Leu-Val-Agly-Ileu-Val-OMe Drug Info [15]
Z-Arg-Leu-Val-Agly-Trp-Val-Ala-NH2 Drug Info [15]
Z-Arg-Leu-Val-Agly-Val-Ala-NH2 Drug Info [15]
Z-leu-Val-Agly-Val-OBzl Drug Info [15]
Modulator MIV-710 Drug Info [14]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Lysosome
Osteoclast differentiation
Toll-like receptor signaling pathway
Rheumatoid arthritis
NetPath Pathway TGF_beta_Receptor Signaling Pathway
RANKL Signaling Pathway
IL2 Signaling Pathway
Reactome Collagen degradation
Degradation of the extracellular matrix
Activation of Matrix Metalloproteinases
Trafficking and processing of endosomal TLR
MHC class II antigen presentation
WikiPathways RANKL/RANK Signaling Pathway
Osteoclast Signaling
References
REF 1Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024552)
REF 2From laboratory to pilot plant: the solid-state process development of a highly potent cathepsin S/K inhibitor. Eur J Pharm Biopharm. 2013 Apr;83(3):436-48.
REF 3Velcura Therapeutics, Inc. to Begin Clinical Trials in Rheumatoid Arthritis Patients. Velcura Therapeutics, Inc. JANUARY 07, 2009.
REF 4Current and future treatments of bone metastases. Expert Opin Emerg Drugs. 2008 Dec;13(4):609-27.
REF 5(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7861).
REF 6ClinicalTrials.gov (NCT00532337) Controlled Study of ONO-5334 in Postmenopausal Women With Osteopenia or Osteoporosis. U.S. National Institutes of Health.
REF 7(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7862).
REF 8Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016480)
REF 9Bioorg 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?.
REF 10J 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.
REF 11How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 12Bioorg 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.
REF 13Bioorg 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.
REF 14(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 2350).
REF 15J 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.
REF 16Bioorg Med Chem. 2009 Feb 1;17(3):1064-70. Epub 2008 Feb 7.Substrate optimization for monitoring cathepsin C activity in live cells.
REF 17J 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.
REF 18The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008 Feb 1;18(3):923-8. Epub 2008 Jan 15.
REF 19Medivir designates MIV-710 a Candidate Drug (CD) for Osteoporosis and Osteoarthritis, 2009
REF 20J Med Chem. 2006 Feb 9;49(3):1066-79.Beta-substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K.
REF 21J Med Chem. 2005 Dec 1;48(24):7688-707.Interaction of papain-like cysteine proteases with dipeptide-derived nitriles.
REF 22Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther. 2008 Jan;83(1):172-6. Epub 2007 Dec 12.
REF 23A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth. Oncol Rep. 2013 May;29(5):2011-8.
REF 24New approach for osteoporosis treatment: cathepsin K inhibitor, ONO-5334. Clin Calcium. 2011 Jan;21(1):64-9.
REF 25Population pharmacokinetic and pharmacodynamic modeling of different formulations of ONO-5334, cathepsin K inhibitor, in Caucasian and Japanese postmenopausal females. J Clin Pharmacol. 2014 Jan;54(1):23-34.
REF 26Bioorg 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.
REF 27Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo. J Bone Miner Res. 1997 Sep;12(9):1396-406.
REF 28Bioorg Med Chem Lett. 2005 Jun 15;15(12):3039-43.Acyclic cyanamide-based inhibitors of cathepsin K.
REF 29Structure 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.
REF 30A 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.
REF 31The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
REF 32Discovery and parallel synthesis of a new class of cathepsin K inhibitors. Bioorg Med Chem Lett. 2001 Nov 19;11(22):2951-4.

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