Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTDZN01)

• DTT Name: Cathepsin K (CTSK)
• Synonyms: Cathepsin X; Cathepsin O2; Cathepsin O; CTSO2; CTSO
• Gene Name: CTSK
• DTT Type: Clinical trial target; [1]
• Related Disease: Low bone mass disorder [ICD-11: FB83]
• BioChemical Class: Peptidase
• UniProt ID: CATK_HUMAN
• TTD ID: T11388
• EC Number: EC 3.4.22.38
• Sequence:
  MWGLKVLLLPVVSFALYPEEILDTHWELWKKTHRKQYNNKVDEISRRLIWEKNLKYISIH
  NLEASLGVHTYELAMNHLGDMTSEEVVQKMTGLKVPLSHSRSNDTLYIPEWEGRAPDSVD
  YRKKGYVTPVKNQGQCGSCWAFSSVGALEGQLKKKTGKLLNLSPQNLVDCVSENDGCGGG
  YMTNAFQYVQKNRGIDSEDAYPYVGQEESCMYNPTGKAAKCRGYREIPEGNEKALKRAVA
  RVGPVSVAIDASLTSFQFYSKGVYYDESCNSDNLNHAVLAVGYGIQKGNKHWIIKNSWGE
  NWGNKGYILMARNKNNACGIANLASFPKM
• Function: Displays potent endoprotease activity against fibrinogen at acid pH. May play an important role in extracellular matrix degradation. Closely involved in osteoclastic bone resorption and may participate partially in the disorder of bone remodeling.
• KEGG Pathway:
  Lysosome (hsa04142)
  Osteoclast differentiation (hsa04380)
  Toll-like receptor signaling pathway (hsa04620)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  Activation of Matrix Metalloproteinases (R-HSA-1592389)
  Trafficking and processing of endosomal TLR (R-HSA-1679131)
  MHC class II antigen presentation (R-HSA-2132295)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DTT

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Odanacatib	DM1EO3G	Osteoporosis	FB83.0	Phase 3	[1], [2]
SAR-114137	DMZ1XR5	Pain	MG30-MG3Z	Phase 1	[3]
VEL-0230	DMDSC63	Rheumatoid arthritis	FA20	Phase 1	[4]

8 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Oxotetrahydro-2-H-furo[3.2-b]pyrrol-4(5-H)-yl derivative 1	DM1SH5R	Pain	MG30-MG3Z	Patented	[5]
PMID25399719-Compound-17	DMRXKJZ	N. A.	N. A.	Patented	[6]
PMID27998201-Compound-10	DMVXTIL	Osteoporosis	FB83.0	Patented	[5]
PMID27998201-Compound-12	DM8QZNC	Bone cancer	2B5Z	Patented	[5]
PMID27998201-Compound-15	DMOB8LU	Pain	MG30-MG3Z	Patented	[5]
PMID27998201-Compound-5	DMVZ0ND	Chronic obstructive pulmonary disease	CA22	Patented	[5]
PMID27998201-Compound-8	DMZK0SY	N. A.	N. A.	Patented	[5]
PMID27998201-Compound-9	DM1JOZN	Rheumatoid arthritis	FA20	Patented	[5]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Balicatib	DM06JTL	Osteoporosis	FB83.0	Discontinued in Phase 2	[7]
ONO-5334	DMWS7C2	Osteoporosis	FB83.0	Discontinued in Phase 2	[8], [9]
Relacatib	DMLJEFH	Bone metastases	2D50	Discontinued in Phase 2	[10], [11], [12]
MIV-701	DM23KBM	Osteoporosis	FB83.0	Discontinued in Phase 1	[13]

2 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GW-2592X	DMNAT5V	Osteoporosis	FB83.0	Preclinical	[14]
L-006235-1	DMMEH12	Osteoarthritis	FA00-FA05	Preclinical	[15]

48 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(S)-1-benzylcyclopentyl 1-oxohexan-2-ylcarbamate	DMICUQK	Discovery agent	N.A.	Investigative	[16]
(S)-tert-butyl 1-oxohexan-2-ylcarbamate	DMAQX4K	Discovery agent	N.A.	Investigative	[16]
(S)-tert-butyl 4-methyl-1-oxopentan-2-ylcarbamate	DMR1HQ3	Discovery agent	N.A.	Investigative	[16]
2-cyclohexylamino-pyridine-2-carbonitrile	DMFMZRB	Discovery agent	N.A.	Investigative	[17]
2-cyclohexylamino-pyrimidine-4-carbonitrile	DMMIGXO	Discovery agent	N.A.	Investigative	[17]
3-Amino-5-Phenylpentane	DMHDFZE	Discovery agent	N.A.	Investigative	[18]
4-cycloheptyl-6-propylpyrimidine-2-carbonitrile	DMNT5BF	Discovery agent	N.A.	Investigative	[19]
4-cyclohexyl-6-propylpyrimidine-2-carbonitrile	DM10U6S	Discovery agent	N.A.	Investigative	[19]
4-cyclohexylamino-pyrimidine-2-carbonitrile	DMGVIXW	Discovery agent	N.A.	Investigative	[17]
4-cyclooctyl-6-propylpyrimidine-2-carbonitrile	DMS42TN	Discovery agent	N.A.	Investigative	[19]
4-phenyl-6-propylpyrimidine-2-carbonitrile	DMMIB0R	Discovery agent	N.A.	Investigative	[20]
4-propyl-6-m-tolylpyrimidine-2-carbonitrile	DMNM4GE	Discovery agent	N.A.	Investigative	[20]
AM-3701	DMZVLJH	Bone metastases	2D50	Investigative	[14]
BF/PC-21	DMCWB1V	Inflammation	1A00-CA43.1	Investigative	[14]
Boc-Agly-Val-Agly-OEt	DMDX8M3	Discovery agent	N.A.	Investigative	[21]
GNF-PF-5434	DMP9AIH	Discovery agent	N.A.	Investigative	[22]
L-873724	DMUP516	Asthma	CA23	Investigative	[10]
MIV-710	DM13TUY	Bone metastases	2D50	Investigative	[14]
N-(1-((cyanomethyl)carbamoyl)cyclohexyl)benzamide	DMBQ5NS	Discovery agent	N.A.	Investigative	[23]
N-(4-phenylbenzoyl)-phenylalanyl-glycine-nitrile	DMUJS4Y	Discovery agent	N.A.	Investigative	[24]
N-(benzyloxycarbonyl)-leucyl-glycine-nitrile	DMR18YI	Discovery agent	N.A.	Investigative	[24]
N-(cyanomethyl)cyclohex-1-ene-1-carboxamide	DMTKREZ	Discovery agent	N.A.	Investigative	[23]
N-(tert-butoxycarbonyl)-isoleucyl-glycine-nitrile	DMJ0S5C	Discovery agent	N.A.	Investigative	[24]
N-(tert-butoxycarbonyl)-leucyl-glycine-nitrile	DMXYQWG	Discovery agent	N.A.	Investigative	[24]
N-(tert-butoxycarbonyl)-methionyl-glycine-nitrile	DM3I0WZ	Discovery agent	N.A.	Investigative	[24]
N-(tert-butoxycarbonyl)-norleucyl-glycine-nitrile	DMGF4XC	Discovery agent	N.A.	Investigative	[24]
N-(tert-butoxycarbonyl)-norvalyl-glycine-nitrile	DMOP5N7	Discovery agent	N.A.	Investigative	[24]
N-(tert-butoxycarbonyl)-valyl-glycine-nitrile	DMUQBOP	Discovery agent	N.A.	Investigative	[24]
N-acetyl-phenylalanyl-glycine-nitrile	DME8O69	Discovery agent	N.A.	Investigative	[24]
N-benzoyl-phenylalanyl-glycine-nitrile	DMRJ4B1	Discovery agent	N.A.	Investigative	[24]
P2,P3 Ketoamide derivative	DMETL3Z	Discovery agent	N.A.	Investigative	[25]
PMID16290936C1b	DMOP8YM	Discovery agent	N.A.	Investigative	[16]
Pyrrolidine-1-carbonitrile	DM906JK	Discovery agent	N.A.	Investigative	[26]
Tert-butyl (2S)-1-cyanopyrrolidine-2-carboxylate	DM8LI1K	Discovery agent	N.A.	Investigative	[26]
TERT-BUTYL 2-CYANO-2-METHYLHYDRAZINECARBOXYLATE	DMZG5I7	Discovery agent	N.A.	Investigative	[27]
Tert-Butyl(1s)-1-Cyclohexyl-2-Oxoethylcarbamate	DM42WFH	Discovery agent	N.A.	Investigative	[27]
Z-Ala-Leu-His-Agly-Ile-Val-OMe	DMMP0DT	Discovery agent	N.A.	Investigative	[21]
Z-Ala-Leu-lle-Agly-Ile-Val-NHBzl	DM7IGRT	Discovery agent	N.A.	Investigative	[21]
Z-Ala-Leu-lle-Agly-Ile-Val-OMe	DMVEUOL	Discovery agent	N.A.	Investigative	[21]
Z-Ala-Leu-Nal-Agly-Ile-Val-OMe	DM3209T	Discovery agent	N.A.	Investigative	[21]
Z-Ala-Leu-Phe-Agly-Ile-Val-OMe	DML16BT	Discovery agent	N.A.	Investigative	[21]
Z-Ala-Leu-Tyr(Me)-Agly-Ile-Val-OMe	DMIB5O3	Discovery agent	N.A.	Investigative	[21]
Z-Arg-Leu-Val-Agly-Ala-Gly-NH2	DM69FKN	Discovery agent	N.A.	Investigative	[21]
Z-Arg-Leu-Val-Agly-Ile-Val-Trp-NH2	DMZDGJO	Discovery agent	N.A.	Investigative	[21]
Z-Arg-Leu-Val-Agly-Ileu-Val-OMe	DMT0UZ1	Discovery agent	N.A.	Investigative	[21]
Z-Arg-Leu-Val-Agly-Trp-Val-Ala-NH2	DMM5O2V	Discovery agent	N.A.	Investigative	[21]
Z-Arg-Leu-Val-Agly-Val-Ala-NH2	DMTWNH7	Discovery agent	N.A.	Investigative	[21]
Z-leu-Val-Agly-Val-OBzl	DM6OGR9	Discovery agent	N.A.	Investigative	[21]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Osteoporosis	FA20	Bone marrow	2.85E-01	-1.14	-2.61
Rheumatoid arthritis	FA20	Synovial tissue	6.91E-04	1.59	1.81

The Drug-Metabolizing Enzyme (DME) Role of This DTT

• DTT DME Name: Cathepsin K (CTSK) DME Info
• Gene Name: CTSK

1 Clinical Trial Drug(s) Metabolized by This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bradykinin	DM4R6UV	N. A.	N. A.	Phase 1	[28]

References

• [1] A novel c-Met inhibitor, MK8033, synergizes with carboplatin plus paclitaxel to inhibit ovarian cancer cell growth. Oncol Rep. 2013 May;29(5):2011-8.
• [2] Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther. 2008 Jan;83(1):172-6.
• [3] From 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.
• [4] Discovery and parallel synthesis of a new class of cathepsin K inhibitors. Bioorg Med Chem Lett. 2001 Nov 19;11(22):2951-4.
• [5] Cathepsin B and L inhibitors: a patent review (2010 - present).Expert Opin Ther Pat. 2017 Jun;27(6):643-656.
• [6] An updated patent review of calpain inhibitors (2012 - 2014).Expert Opin Ther Pat. 2015 Jan;25(1):17-31.
• [7] Current and future treatments of bone metastases. Expert Opin Emerg Drugs. 2008 Dec;13(4):609-27.
• [8] New approach for osteoporosis treatment: cathepsin K inhibitor, ONO-5334. Clin Calcium. 2011 Jan;21(1):64-9.
• [9] Population 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.
• [10] The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008 Feb 1;18(3):923-8.
• [11] A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone tur... Bone. 2007 Jan;40(1):122-31.
• [12] Structure 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.
• [13] Medivir designates MIV-710 a Candidate Drug (CD) for Osteoporosis and Osteoarthritis, 2009
• [14] URL: 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).
• [15] Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional se... J Med Chem. 2005 Dec 1;48(24):7535-43.
• [16] Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors Bioorg Med Chem Lett. 2006 Feb 15;16(4):978-83.
• [17] 2-Cyano-pyrimidines: a new chemotype for inhibitors of the cysteine protease cathepsin K. J Med Chem. 2007 Feb 22;50(4):591-4.
• [18] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [19] Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors. Bioorg Med Chem Lett. 2010 Mar 1;20(5):1524-7.
• [20] 2-Phenyl-9H-purine-6-carbonitrile derivatives as selective cathepsin S inhibitors. Bioorg Med Chem Lett. 2010 Aug 1;20(15):4447-50.
• [21] Azapeptides structurally based upon inhibitory sites of cystatins as potent and selective inhibitors of cysteine proteases. J Med Chem. 2002 Sep 12;45(19):4202-11.
• [22] Substrate optimization for monitoring cathepsin C activity in live cells. Bioorg Med Chem. 2009 Feb 1;17(3):1064-70.
• [23] Beta-substituted cyclohexanecarboxamide: a nonpeptidic framework for the design of potent inhibitors of cathepsin K. J Med Chem. 2006 Feb 9;49(3):1066-79.
• [24] Interaction of papain-like cysteine proteases with dipeptide-derived nitriles. J Med Chem. 2005 Dec 1;48(24):7688-707.
• [25] Potent and selective P2-P3 ketoamide inhibitors of cathepsin K with good pharmacokinetic properties via favorable P1', P1, and/or P3 substitutions. Bioorg Med Chem Lett. 2004 Oct 4;14(19):4897-902.
• [26] Acyclic cyanamide-based inhibitors of cathepsin K. Bioorg Med Chem Lett. 2005 Jun 15;15(12):3039-43.
• [27] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [28] A cysteine-type carboxypeptidase, cathepsin X, generates peptide receptor agonists. Int Immunopharmacol. 2010 Jan;10(1):134-9.