Target Information

Target General Information

Target ID

T57943 (Former ID: TTDR00440)

Target 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

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Brain cancer [ICD-11: 2A00]

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.

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BioChemical Class

Peptidase

UniProt ID

CASP3_HUMAN

EC Number

EC 3.4.22.56

Sequence

MENTENSVDSKSIKNLEPKIIHGSESMDSGISLDNSYKMDYPEMGLCIIINNKNFHKSTG
MTSRSGTDVDAANLRETFRNLKYEVRNKNDLTREEIVELMRDVSKEDHSKRSSFVCVLLS
HGEEGIIFGTNGPVDLKKITNFFRGDRCRSLTGKPKLFIIQACRGTELDCGIETDSGVDD
DMACHKIPVEADFLYAYSTAPGYYSWRNSKDGSWFIQSLCAMLKQYADKLEFMHILTRVN
RKVATEFESFSFDATFHAKKQIPCIVSMLTKELYFYH

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3D Structure

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PDB

ADReCS ID

BADD_A05213 ; BADD_A05311 ; BADD_A05519 ; BADD_A05675 ; BADD_A08298

HIT2.0 ID

T85U8U

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

PAC1

Drug Info

Phase 1

Anaplastic astrocytoma

[2], [3]

Mode of Action

[+] 3 Modes of Action

Activator

[+] 2 Activator drugs

PAC1

Drug Info

[1]

PETCM

Drug Info

[11]

Inhibitor

[+] 16 Inhibitor drugs

2-(4-fluoro-benzyl)isoquinoline-1,3,4-trione

Drug Info

[4]

2-(4-methoxy-benzyl)isoquinoline-1,3,4-trione

Drug Info

[4]

2-allylisoquinoline-1,3,4-trione

Drug Info

[4]

2-benzylisoquinoline-1,3,4-trione

Drug Info

[4]

2-methylisoquinoline-1,3,4-trione

Drug Info

[4]

2-phenethylisoquinoline-1,3,4-trione

Drug Info

[4]

5-(azepan-1-ylsulfonyl)indoline-2,3-dione

Drug Info

[5]

5-(azetidin-1-ylsulfonyl)indoline-2,3-dione

Drug Info

[5]

5-(piperidin-1-ylsulfonyl)indoline-2,3-dione

Drug Info

[5]

5-(pyrrolidin-1-ylsulfonyl)indoline-2,3-dione

Drug Info

[5]

Ac-Asp-Glu-Val-Asp-CHO

Drug Info

[6]

Ac-DEVD-CHO

Drug Info

[7]

AZ10417808

Drug Info

[8]

Isoquinoline-1,3,4(2H)-trione

Drug Info

[4]

M826

Drug Info

[10]

SJ-8002

Drug Info

[12]

Modulator

[+] 1 Modulator drugs

Glionitrin A

Drug Info

[9]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 25 KEGG Pathways	+
1	MAPK signaling pathway
2	p53 signaling pathway
3	Apoptosis
4	Natural killer cell mediated cytotoxicity
5	TNF signaling pathway
6	Serotonergic synapse
7	Non-alcoholic fatty liver disease (NAFLD)
8	Alzheimer's disease
9	Parkinson's disease
10	Amyotrophic lateral sclerosis (ALS)
11	Huntington's disease
12	Epithelial cell signaling in Helicobacter pylori infection
13	Pertussis
14	Legionellosis
15	Toxoplasmosis
16	Amoebiasis
17	Tuberculosis
18	Hepatitis B
19	Herpes simplex infection
20	Pathways in cancer
21	Viral carcinogenesis
22	Proteoglycans in cancer
23	MicroRNAs in cancer
24	Colorectal cancer
25	Viral myocarditis
NetPath Pathway	[+] 3 NetPath Pathways	+
1	TCR Signaling Pathway
2	IL2 Signaling Pathway
3	IL4 Signaling Pathway
Panther Pathway	[+] 4 Panther Pathways	+
1	Apoptosis signaling pathway
2	FAS signaling pathway
3	Huntington disease
4	CCKR signaling map ST
PID Pathway	[+] 9 PID Pathways	+
1	LPA receptor mediated events
2	Calcineurin-regulated NFAT-dependent transcription in lymphocytes
3	FAS (CD95) signaling pathway
4	Role of Calcineurin-dependent NFAT signaling in lymphocytes
5	Posttranslational regulation of adherens junction stability and dissassembly
6	p75(NTR)-mediated signaling
7	HIV-1 Nef: Negative effector of Fas and TNF-alpha
8	Caspase Cascade in Apoptosis
9	Syndecan-2-mediated signaling events
Reactome	[+] 7 Reactome Pathways	+
1	SMAC binds to IAPs
2	SMAC-mediated dissociation of IAP:caspase complexes
3	Apoptotic cleavage of cellular proteins
4	Degradation of the extracellular matrix
5	NADE modulates death signalling
6	Activation of DNA fragmentation factor
7	Caspase-mediated cleavage of cytoskeletal proteins
WikiPathways	[+] 29 WikiPathways	+
1	DNA Damage Response
2	SIDS Susceptibility Pathways
3	Apoptosis Modulation by HSP70
4	MAPK Signaling Pathway
5	Copper homeostasis
6	FAS pathway and Stress induction of HSP regulation
7	Signaling by Hippo
8	Apoptosis
9	Amyotrophic lateral sclerosis (ALS)
10	Spinal Cord Injury
11	BDNF signaling pathway
12	Integrated Pancreatic Cancer Pathway
13	Oncostatin M Signaling Pathway
14	Parkinsons Disease Pathway
15	Corticotropin-releasing hormone
16	Allograft Rejection
17	AGE/RAGE pathway
18	TNF alpha Signaling Pathway
19	Prostate Cancer
20	Alzheimers Disease
21	TWEAK Signaling Pathway
22	Integrated Breast Cancer Pathway
23	Signalling by NGF
24	Integrated Cancer pathway
25	Regulation of Apoptosis
26	Intrinsic Pathway for Apoptosis
27	Apoptotic execution phase
28	Apoptosis Modulation and Signaling
29	miRNA Regulation of DNA Damage Response

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Small-molecule activation of procaspase-3 to caspase-3 as a personalized anticancer strategy. Nat Chem Biol. 2006 Oct;2(10):543-50.

REF 2

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 3

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 4

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.

REF 5

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.

REF 6

Design and synthesis of a potent and selective peptidomimetic inhibitor of caspase-3. J Med Chem. 2004 Dec 16;47(26):6455-8.

REF 7

Synthesis and evaluation of vinyl sulfones as caspase-3 inhibitors. A structure-activity study. Eur J Med Chem. 2010 Sep;45(9):3858-63.

REF 8

Novel small molecule inhibitors of caspase-3 block cellular and biochemical features of apoptosis. J Pharmacol Exp Ther. 2003 Jan;304(1):433-40.

REF 9

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.

REF 10

Novel pyrazinone mono-amides as potent and reversible caspase-3 inhibitors. Bioorg Med Chem Lett. 2005 Feb 15;15(4):1173-80.

REF 11

Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science. 2003 Jan 10;299(5604):223-6.

REF 12

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).

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