Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTG5QB7)

• DTT Name: Calpain-2 (CAPN2)
• Synonyms: Millimolar-calpain; M-calpain; Calpain-2 large subunit; Calpain-2 catalytic subunit; Calpain large polypeptide L2; Calpain M-type; Calcium-activated neutral proteinase 2; Calcium-activated neutral proteinase; CANPL2; CANP 2; CANP
• Gene Name: CAPN2
• DTT Type: Clinical trial target; [1]
• Related Disease: Alzheimer disease [ICD-11: 8A20]
• BioChemical Class: Peptidase
• UniProt ID: CAN2_HUMAN
• TTD ID: T04902
• EC Number: EC 3.4.22.53
• Sequence:
  MAGIAAKLAKDREAAEGLGSHDRAIKYLNQDYEALRNECLEAGTLFQDPSFPAIPSALGF
  KELGPYSSKTRGIEWKRPTEICADPQFIIGGATRTDICQGALGDCWLLAAIASLTLNEEI
  LARVVPLNQSFQENYAGIFHFQFWQYGEWVEVVVDDRLPTKDGELLFVHSAEGSEFWSAL
  LEKAYAKINGCYEALSGGATTEGFEDFTGGIAEWYELKKPPPNLFKIIQKALQKGSLLGC
  SIDITSAADSEAITFQKLVKGHAYSVTGAEEVESNGSLQKLIRIRNPWGEVEWTGRWNDN
  CPSWNTIDPEERERLTRRHEDGEFWMSFSDFLRHYSRLEICNLTPDTLTSDTYKKWKLTK
  MDGNWRRGSTAGGCRNYPNTFWMNPQYLIKLEEEDEDEEDGESGCTFLVGLIQKHRRRQR
  KMGEDMHTIGFGIYEVPEELSGQTNIHLSKNFFLTNRARERSDTFINLREVLNRFKLPPG
  EYILVPSTFEPNKDGDFCIRVFSEKKADYQAVDDEIEANLEEFDISEDDIDDGFRRLFAQ
  LAGEDAEISAFELQTILRRVLAKRQDIKSDGFSIETCKIMVDMLDSDGSGKLGLKEFYIL
  WTKIQKYQKIYREIDVDRSGTMNSYEMRKALEEAGFKMPCQLHQVIVARFADDQLIIDFD
  NFVRCLVRLETLFKIFKQLDPENTGTIELDLISWLCFSVL
• Function: Proteolytically cleaves MYOC at 'Arg-226'. Proteolytically cleaves CPEB3 following neuronal stimulation which abolishes CPEB3 translational repressor activity, leading to translation of CPEB3 target mRNAs. Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction.
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  Apoptosis (hsa04210)
  Alzheimer's disease (hsa05010)
• Reactome Pathway: Degradation of the extracellular matrix (R-HSA-1474228)

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
ABT-957	DMB9N4J	Alzheimer disease	8A20	Phase 1	[1]

19 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
5-azolone derivative 1	DMN2B87	N. A.	N. A.	Patented	[2]
Carboxamide derivative 10	DM5WMO9	N. A.	N. A.	Patented	[2]
Carboxamide derivative 11	DM1DN94	N. A.	N. A.	Patented	[2]
Carboxamide derivative 5	DM149WN	N. A.	N. A.	Patented	[2]
Carboxamide derivative 6	DM6GZW4	N. A.	N. A.	Patented	[2]
Carboxamide derivative 7	DM8TQS4	N. A.	N. A.	Patented	[2]
Carboxamide derivative 8	DM6HI34	N. A.	N. A.	Patented	[2]
Carboxamide derivative 9	DMVISYC	N. A.	N. A.	Patented	[2]
Epoxysuccinate derivative 1	DMU8LPN	N. A.	N. A.	Patented	[2]
Epoxysuccinate derivative 10	DMYF39U	N. A.	N. A.	Patented	[2]
Epoxysuccinate derivative 2	DMEV9O3	N. A.	N. A.	Patented	[2]
Epoxysuccinate derivative 3	DMMETW5	N. A.	N. A.	Patented	[2]
Epoxysuccinate derivative 4	DMCF6M8	N. A.	N. A.	Patented	[2]
Epoxysuccinate derivative 5	DM37MCN	N. A.	N. A.	Patented	[2]
Epoxysuccinate derivative 6	DMQM6ZS	N. A.	N. A.	Patented	[2]
Epoxysuccinate derivative 7	DMTSPVF	N. A.	N. A.	Patented	[2]
Epoxysuccinate derivative 8	DMQTVPC	N. A.	N. A.	Patented	[2]
Epoxysuccinate derivative 9	DM49FU0	N. A.	N. A.	Patented	[2]
PMID25399719-Compound-17	DMRXKJZ	N. A.	N. A.	Patented	[2]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bithionol	DMPJKRL	Trematode infection	1F8Y	Withdrawn from market	[3]
Aloxistatin	DMGW07M	Neurological disorder	6B60	Discontinued in Phase 3	[3]
AK-295	DM51NI0	Cerebral infarction	8B11.5Z	Terminated	[4]
MDL-28170	DMYK31O	Alzheimer disease	8A20	Terminated	[5]
SJA-6017	DM6X430	N. A.	N. A.	Terminated	[6]

12 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(1-Benzyl-2-oxo-ethyl)-carbamic acid benzyl ester	DMWK3RO	Discovery agent	N.A.	Investigative	[7]
3-(1H-Pyrrol-3-yl)-propionamide	DMCKJ27	Discovery agent	N.A.	Investigative	[8]
A-558693	DMN320E	Neurological disorder	6B60	Investigative	[4]
AW-00430	DMG6LJ8	Discovery agent	N.A.	Investigative	[3]
Calpastatin	DMR0CNQ	Discovery agent	N.A.	Investigative	[9], [10]
DIHYDROXANTHOHUMOL	DMFKWRM	Discovery agent	N.A.	Investigative	[3]
GNF-PF-4453	DMPYIA3	Discovery agent	N.A.	Investigative	[3]
mercaptoacrylate inhibitor of calpain 1	DMZIA1R	Discovery agent	N.A.	Investigative	[4]
N-(1-Benzyl-2-oxo-ethyl)-benzamide	DMP9A7L	Discovery agent	N.A.	Investigative	[7]
PMID20690647C4b	DMKVONZ	Discovery agent	N.A.	Investigative	[11]
PMID20690647C5a	DMRWZX6	Discovery agent	N.A.	Investigative	[11]
PMID8831774C19	DMM08LV	Discovery agent	N.A.	Investigative	[12]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	5.15E-14	0.35	1.04

References

• [1] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [2] An updated patent review of calpain inhibitors (2012 - 2014).Expert Opin Ther Pat. 2015 Jan;25(1):17-31.
• [3] In silico identification and biochemical evaluation of novel inhibitors of NRH:quinone oxidoreductase 2 (NQO2). Bioorg Med Chem Lett. 2010 Dec 15;20(24):7331-6.
• [4] 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: 2336).
• [5] Synthesis of a small library of diketopiperazines as potential inhibitors of calpain. Bioorg Med Chem Lett. 2005 Jun 15;15(12):3034-8.
• [6] Synthesis, biological evaluation and molecular modelling of N-heterocyclic dipeptide aldehydes as selective calpain inhibitors. Bioorg Med Chem. 2008 Jul 15;16(14):6911-23.
• [7] Alpha-diketone and alpha-keto ester derivatives of N-protected amino acids and peptides as novel inhibitors of cysteine and serine proteinases. J Med Chem. 1990 Jan;33(1):11-3.
• [8] Synthesis of cystamidin a (pyrrole-3-propanamide), a reported calpain inhibitor, Bioorg. Med. Chem. Lett. 6(13):1541-1542 (1996).
• [9] Calpain in the pathophysiology of spinal cord injury: neuroprotection with calpain inhibitors. Brain Res Brain Res Rev. 2003 May;42(2):169-85.
• [10] PEST sequences in the malaria parasite Plasmodium falciparum: a genomic study. Malar J. 2003 Jun 23;2:16.
• [11] Peptidyl alpha-ketoamides with nucleobases, methylpiperazine, and dimethylaminoalkyl substituents as calpain inhibitors. J Med Chem. 2010 Sep 9;53(17):6326-36.
• [12] Novel peptidyl alpha-keto amide inhibitors of calpains and other cysteine proteases. J Med Chem. 1996 Sep 27;39(20):4089-98.