Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT36ETB)

• DTT Name: Cathepsin L (CTSL)
• Synonyms: Major excreted protein; MEP; Cathepsin L1; CTSL1
• Gene Name: CTSL
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: CATL1_HUMAN
• TTD ID: T41141
• EC Number: EC 3.4.22.15
• Sequence:
  MNPTLILAAFCLGIASATLTFDHSLEAQWTKWKAMHNRLYGMNEEGWRRAVWEKNMKMIE
  LHNQEYREGKHSFTMAMNAFGDMTSEEFRQVMNGFQNRKPRKGKVFQEPLFYEAPRSVDW
  REKGYVTPVKNQGQCGSCWAFSATGALEGQMFRKTGRLISLSEQNLVDCSGPQGNEGCNG
  GLMDYAFQYVQDNGGLDSEESYPYEATEESCKYNPKYSVANDTGFVDIPKQEKALMKAVA
  TVGPISVAIDAGHESFLFYKEGIYFEPDCSSEDMDHGVLVVGYGFESTESDNNKYWLVKN
  SWGEEWGMGGYVKMAKDRRNHCGIASAASYPTV
• Function: Important for the overall degradation of proteins in lysosomes.
• KEGG Pathway:
  Lysosome (hsa04142)
  Phagosome (hsa04145)
  Antigen processing and presentation (hsa04612)
  Proteoglycans in cancer (hsa05205)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  Collagen degradation (R-HSA-1442490)
  Degradation of the extracellular matrix (R-HSA-1474228)
  Trafficking and processing of endosomal TLR (R-HSA-1679131)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)
  MHC class II antigen presentation (R-HSA-2132295)
  Endosomal/Vacuolar pathway (R-HSA-1236977)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
KGP94	DM2NZ6K	Coagulation defect	3B10.0	Clinical trial	[1]

10 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Phenylalanine derivative 1	DMVYP8K	Glioma	2A00.0	Patented	[2]
PMID25399719-Compound-17	DMRXKJZ	N. A.	N. A.	Patented	[3]
PMID27998201-Compound-1	DM5QH4C	Coronavirus infection	1D92	Patented	[2]
PMID27998201-Compound-12	DM8QZNC	Bone cancer	2B5Z	Patented	[2]
PMID27998201-Compound-17	DMAZVHJ	Hair loss	ED70	Patented	[2]
PMID27998201-Compound-19	DM67RMX	Solid tumour/cancer	2A00-2F9Z	Patented	[2]
PMID27998201-Compound-5	DMVZ0ND	Chronic obstructive pulmonary disease	CA22	Patented	[2]
PMID27998201-Compound-6	DM0LGTY	N. A.	N. A.	Patented	[2]
PMID27998201-Compound-7	DMU4QYR	Abdominal aortic aneurysm	BD50.4	Patented	[2]
PMID27998201-Compound-9	DM1JOZN	Rheumatoid arthritis	FA20	Patented	[2]

6 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CLIK-148	DM0BHL8	Rheumatoid arthritis	FA20	Preclinical	[4]
CLIK-181	DMXKN6R	Rheumatoid arthritis	FA20	Preclinical	[5]
L-006235-1	DMMEH12	Osteoarthritis	FA00-FA05	Preclinical	[6]
SD1002	DMLAF6C	Alzheimer disease	8A20	Preclinical	[5]
SD1003	DM29BW1	Alzheimer disease	8A20	Preclinical	[5]
Z-Phe-Ala-diazomethylketone	DMX23CZ	Alzheimer disease	8A20	Preclinical	[5]

28 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(3-Bromobenzoylpyridine)thiosemicarbazone	DMHF01G	Discovery agent	N.A.	Investigative	[1]
(S)-1-benzylcyclopentyl 1-oxohexan-2-ylcarbamate	DMICUQK	Discovery agent	N.A.	Investigative	[7]
(S)-tert-butyl 1-oxohexan-2-ylcarbamate	DMAQX4K	Discovery agent	N.A.	Investigative	[7]
1-(1,3-diphenylpropylidene)thiosemicarbazide	DMYI3F5	Discovery agent	N.A.	Investigative	[8]
1-(phenyl(p-tolyl)methylene)thiosemicarbazide	DMU10CY	Discovery agent	N.A.	Investigative	[8]
6-(benzylamino)-9-butyl-9H-purine-2-carbonitrile	DM7BIJH	Discovery agent	N.A.	Investigative	[9]
9-benzyl-6-(benzylamino)-9H-purine-2-carbonitrile	DMUMOE2	Discovery agent	N.A.	Investigative	[9]
BIPHENYL-4-YL-ACETALDEHYDE	DM5DPHO	Discovery agent	N.A.	Investigative	[10]
Bis(3-bromophenyl)(4-hydroxy)thiosemicarbazone	DM784AU	Discovery agent	N.A.	Investigative	[1]
Bis(3-bromophenyl)(5-hydroxy)thiosemicarbazone	DMASNGX	Discovery agent	N.A.	Investigative	[1]
Bis(3-Fluorophenyl)-ketone]thiosemicarbazone	DMMJ635	Discovery agent	N.A.	Investigative	[11]
CAA0225	DMQATPN	Discovery agent	N.A.	Investigative	[12]
Cysteinesulfonic Acid	DMXI8FP	Discovery agent	N.A.	Investigative	[13]
L-873724	DMUP516	Asthma	CA23	Investigative	[14]
N-(4-phenylbenzoyl)-phenylalanyl-glycine-nitrile	DMUJS4Y	Discovery agent	N.A.	Investigative	[15]
N-(benzyloxycarbonyl)-leucyl-glycine-nitrile	DMR18YI	Discovery agent	N.A.	Investigative	[15]
N-(tert-butoxycarbonyl)-isoleucyl-glycine-nitrile	DMJ0S5C	Discovery agent	N.A.	Investigative	[15]
N-(tert-butoxycarbonyl)-leucyl-glycine-nitrile	DMXYQWG	Discovery agent	N.A.	Investigative	[15]
N-(tert-butoxycarbonyl)-methionyl-glycine-nitrile	DM3I0WZ	Discovery agent	N.A.	Investigative	[15]
N-(tert-butoxycarbonyl)-norleucyl-glycine-nitrile	DMGF4XC	Discovery agent	N.A.	Investigative	[15]
N-(tert-butoxycarbonyl)-tyrosyl-glycine-nitrile	DMP9JVT	Discovery agent	N.A.	Investigative	[15]
N-(tert-butoxycarbonyl)-valyl-glycine-nitrile	DMUQBOP	Discovery agent	N.A.	Investigative	[15]
N-acetyl-phenylalanyl-glycine-nitrile	DME8O69	Discovery agent	N.A.	Investigative	[15]
N-benzoyl-phenylalanyl-glycine-nitrile	DMRJ4B1	Discovery agent	N.A.	Investigative	[15]
Peptide alpha-keto-beta-aldehyde-based inhibitors	DMC6GUA	Discovery agent	N.A.	Investigative	[16]
[(3-Bromophenyl)-m-tolyl-ketone]thiosemicarbazone	DMTK9V7	Discovery agent	N.A.	Investigative	[11]
[(3-Bromophenyl)-p-tolyl-ketone]thiosemicarbazone	DMZG7TH	Discovery agent	N.A.	Investigative	[11]
[2-Phenylacetophenone]thiosemicarbazone	DM4WXD2	Discovery agent	N.A.	Investigative	[1]

References

• [1] Functionalized benzophenone, thiophene, pyridine, and fluorene thiosemicarbazone derivatives as inhibitors of cathepsin L. Bioorg Med Chem Lett. 2010 Nov 15;20(22):6610-5.
• [2] Cathepsin B and L inhibitors: a patent review (2010 - present).Expert Opin Ther Pat. 2017 Jun;27(6):643-656.
• [3] An updated patent review of calpain inhibitors (2012 - 2014).Expert Opin Ther Pat. 2015 Jan;25(1):17-31.
• [4] Structure-based development of specific inhibitors for individual cathepsins and their medical applications. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(2):29-39.
• [5] Lysosomes as a therapeutic target. Nat Rev Drug Discov. 2019 Dec;18(12):923-948.
• [6] 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.
• [7] Semicarbazone-based inhibitors of cathepsin K, are they prodrugs for aldehyde inhibitors Bioorg Med Chem Lett. 2006 Feb 15;16(4):978-83.
• [8] Discovery of trypanocidal thiosemicarbazone inhibitors of rhodesain and TbcatB. Bioorg Med Chem Lett. 2008 May 1;18(9):2883-5.
• [9] Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB. J Med Chem. 2008 Feb 14;51(3):545-52.
• [10] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [11] Design, synthesis, and biological evaluation of potent thiosemicarbazone based cathepsin L inhibitors. Bioorg Med Chem Lett. 2010 Feb 15;20(4):1415-9.
• [12] Characterization of CAA0225, a novel inhibitor specific for cathepsin L, as a probe for autophagic proteolysis. Biol Pharm Bull. 2009 Mar;32(3):475-9.
• [13] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [14] The identification of potent, selective, and bioavailable cathepsin S inhibitors. Bioorg Med Chem Lett. 2007 Sep 1;17(17):4929-33.
• [15] Interaction of papain-like cysteine proteases with dipeptide-derived nitriles. J Med Chem. 2005 Dec 1;48(24):7688-707.
• [16] Synthesis and kinetic evaluation of peptide alpha-keto-beta-aldehyde-based inhibitors of trypsin-like serine proteases. J Pharm Pharmacol. 2001 Apr;53(4):473-80.