Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTPF2QI)

• DTT Name: Caspase-3 (CASP3)
• Synonyms: Yama protein; SREBP cleavage activity 1; SCA-1; Protein Yama; Cysteine protease CPP32; Caspase 3; CPP32; CPP-32; CASP-3; Apopain
• Gene Name: CASP3
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: CASP3_HUMAN
• TTD ID: T57943
• EC Number: EC 3.4.22.56
• Sequence:
  MENTENSVDSKSIKNLEPKIIHGSESMDSGISLDNSYKMDYPEMGLCIIINNKNFHKSTG
  MTSRSGTDVDAANLRETFRNLKYEVRNKNDLTREEIVELMRDVSKEDHSKRSSFVCVLLS
  HGEEGIIFGTNGPVDLKKITNFFRGDRCRSLTGKPKLFIIQACRGTELDCGIETDSGVDD
  DMACHKIPVEADFLYAYSTAPGYYSWRNSKDGSWFIQSLCAMLKQYADKLEFMHILTRVN
  RKVATEFESFSFDATFHAKKQIPCIVSMLTKELYFYH
• Function: At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage. Involved in the activation cascade of caspases responsible for apoptosis execution.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  p53 signaling pathway (hsa04115)
  Apoptosis (hsa04210)
  Natural killer cell mediated cytotoxicity (hsa04650)
  TNF signaling pathway (hsa04668)
  Serotonergic synapse (hsa04726)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Alzheimer's disease (hsa05010)
  Parkinson's disease (hsa05012)
  Amyotrophic lateral sclerosis (ALS) (hsa05014)
  Huntington's disease (hsa05016)
  Epithelial cell signaling in Helicobacter pylori infection (hsa05120)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Hepatitis B (hsa05161)
  Herpes simplex infection (hsa05168)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
  Colorectal cancer (hsa05210)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  SMAC-mediated dissociation of IAP (R-HSA-111464)
  Apoptotic cleavage of cellular proteins (R-HSA-111465)
  Degradation of the extracellular matrix (R-HSA-1474228)
  NADE modulates death signalling (R-HSA-205025)
  Activation of DNA fragmentation factor (R-HSA-211227)
  Caspase-mediated cleavage of cytoskeletal proteins (R-HSA-264870)
  SMAC binds to IAPs (R-HSA-111463)

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
PAC1	DMYQUIP	Anaplastic astrocytoma	2A00.0	Phase 1	[1]

18 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(4-fluoro-benzyl)isoquinoline-1,3,4-trione	DMZSHDR	Discovery agent	N.A.	Investigative	[2]
2-(4-methoxy-benzyl)isoquinoline-1,3,4-trione	DMHAE31	Discovery agent	N.A.	Investigative	[2]
2-allylisoquinoline-1,3,4-trione	DM3DE9Z	Discovery agent	N.A.	Investigative	[2]
2-benzylisoquinoline-1,3,4-trione	DME7SAV	Discovery agent	N.A.	Investigative	[2]
2-methylisoquinoline-1,3,4-trione	DMHW9GL	Discovery agent	N.A.	Investigative	[2]
2-phenethylisoquinoline-1,3,4-trione	DMPWG21	Discovery agent	N.A.	Investigative	[2]
5-(azepan-1-ylsulfonyl)indoline-2,3-dione	DMGIO3R	Discovery agent	N.A.	Investigative	[3]
5-(azetidin-1-ylsulfonyl)indoline-2,3-dione	DMJIVLY	Discovery agent	N.A.	Investigative	[3]
5-(piperidin-1-ylsulfonyl)indoline-2,3-dione	DMT60AM	Discovery agent	N.A.	Investigative	[3]
5-(pyrrolidin-1-ylsulfonyl)indoline-2,3-dione	DMJBK7F	Discovery agent	N.A.	Investigative	[3]
Ac-Asp-Glu-Val-Asp-CHO	DM4KQUS	Discovery agent	N.A.	Investigative	[4]
Ac-DEVD-CHO	DMW02H7	Discovery agent	N.A.	Investigative	[5]
AZ10417808	DMNO6PL	Discovery agent	N.A.	Investigative	[6]
Glionitrin A	DM98CSW	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
Isoquinoline-1,3,4(2H)-trione	DMT4RI2	Discovery agent	N.A.	Investigative	[2]
M826	DM9NPE4	Discovery agent	N.A.	Investigative	[8]
PETCM	DM0N1DH	Discovery agent	N.A.	Investigative	[9]
SJ-8002	DMEQBU2	Solid tumour/cancer	2A00-2F9Z	Investigative	[10]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	3.36E-01	0.03	0.05

References

• [1] Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy. Nat Chem Biol. 2006 Oct;2(10):543-50.
• [2] Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors. J Med Chem. 2006 Mar 9;49(5):1613-23.
• [3] Design, synthesis, and discovery of novel non-peptide inhibitor of Caspase-3 using ligand based and structure based virtual screening approach. Bioorg Med Chem. 2009 Aug 15;17(16):6040-7.
• [4] Design and synthesis of a potent and selective peptidomimetic inhibitor of caspase-3. J Med Chem. 2004 Dec 16;47(26):6455-8.
• [5] Synthesis and evaluation of vinyl sulfones as caspase-3 inhibitors. A structure-activity study. Eur J Med Chem. 2010 Sep;45(9):3858-63.
• [6] Novel small molecule inhibitors of caspase-3 block cellular and biochemical features of apoptosis. J Pharmacol Exp Ther. 2003 Jan;304(1):433-40.
• [7] Glionitrin A, a new diketopiperazine disulfide, activates ATM-ATR-Chk1/2 via 53BP1 phosphorylation in DU145 cells and shows antitumor effect in xenograft model. Biol Pharm Bull. 2014;37(3):378-86.
• [8] Novel pyrazinone mono-amides as potent and reversible caspase-3 inhibitors. Bioorg Med Chem Lett. 2005 Feb 15;15(4):1173-80.
• [9] Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science. 2003 Jan 10;299(5604):223-6.
• [10] 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: 1619).