Target Information
| Target General Information | Top | |||||
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| Target ID |
T98269
(Former ID: TTDR00434)
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| Target Name |
Caspase-1 (CASP1)
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| Synonyms |
P45; Interleukin-1 beta-converting enzyme; Interleukin-1 beta converting enzyme; Interleukin-1 beta convertase; IL1BCE; IL1BC; IL-1BC; IL-1 beta-converting enzyme; IL-1 beta converting enzyme; ICE; CASP-1
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| Gene Name |
CASP1
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 4 Target-related Diseases | + | ||||
| 1 | Epilepsy/seizure [ICD-11: 8A61-8A6Z] | |||||
| 2 | Fibrosis [ICD-11: GA14-GC01] | |||||
| 3 | Rheumatoid arthritis [ICD-11: FA20] | |||||
| 4 | Type 2 diabetes mellitus [ICD-11: 5A11] | |||||
| Function |
Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis. Upon inflammasome activation, during DNA virus infection but not RNA virus challenge, controls antiviral immunity through the cleavage of CGAS, rendering it inactive. Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes.
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| BioChemical Class |
Peptidase
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| UniProt ID | ||||||
| EC Number |
EC 3.4.22.36
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| Sequence |
MADKVLKEKRKLFIRSMGEGTINGLLDELLQTRVLNKEEMEKVKRENATVMDKTRALIDS
VIPKGAQACQICITYICEEDSYLAGTLGLSADQTSGNYLNMQDSQGVLSSFPAPQAVQDN PAMPTSSGSEGNVKLCSLEEAQRIWKQKSAEIYPIMDKSSRTRLALIICNEEFDSIPRRT GAEVDITGMTMLLQNLGYSVDVKKNLTASDMTTELEAFAHRPEHKTSDSTFLVFMSHGIR EGICGKKHSEQVPDILQLNAIFNMLNTKNCPSLKDKPKVIIIQACRGDSPGVVWFKDSVG VSGNLSLPTTEEFEDDAIKKAHIEKDFIAFCSSTPDNVSWRHPTMGSVFIGRLIEHMQEY ACSCDVEEIFRKVRFSFEQPDGRAQMPTTERVTLTRCFYLFPGH Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T38OH4 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 4 Clinical Trial Drugs | + | ||||
| 1 | AC-201 | Drug Info | Phase 2 | Type-2 diabetes | [2] | |
| 2 | Belnacasan | Drug Info | Phase 2 | Epilepsy | [3] | |
| 3 | Nivocasan | Drug Info | Phase 2 | Fibrosis | [4] | |
| 4 | PRALNACASAN | Drug Info | Phase 2 | Rheumatoid arthritis | [3], [5] | |
| Patented Agent(s) | [+] 2 Patented Agents | + | ||||
| 1 | Ac-YVAD-cmk | Drug Info | Patented | Photocontact dermatitis | [6] | |
| 2 | Ac-YVAD-FMK | Drug Info | Patented | Photocontact dermatitis | [6] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | SDZ-224-015 | Drug Info | Terminated | Rheumatoid arthritis | [7] | |
| 2 | VE-16084 | Drug Info | Terminated | Rheumatoid arthritis | [8] | |
| Mode of Action | [+] 2 Modes of Action | + | ||||
| Inhibitor | [+] 11 Inhibitor drugs | + | ||||
| 1 | AC-201 | Drug Info | [2] | |||
| 2 | Belnacasan | Drug Info | [1], [9] | |||
| 3 | Ac-YVAD-cmk | Drug Info | [6] | |||
| 4 | Ac-YVAD-FMK | Drug Info | [6] | |||
| 5 | L-709049 | Drug Info | [10] | |||
| 6 | VE-16084 | Drug Info | [8] | |||
| 7 | M826 | Drug Info | [12] | |||
| 8 | YVAD | Drug Info | [13] | |||
| 9 | Z-VAD-CHO | Drug Info | [14] | |||
| 10 | Z-YVAD-CHO | Drug Info | [14] | |||
| 11 | Z-YVAD-FMK | Drug Info | [15] | |||
| Modulator | [+] 3 Modulator drugs | + | ||||
| 1 | Nivocasan | Drug Info | [4] | |||
| 2 | PRALNACASAN | Drug Info | [3] | |||
| 3 | SDZ-224-015 | Drug Info | [11] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: (3S)-4-hydroxy-3-[[(2R)-2-[3-methyl-2,6-dioxo-5-[[4-(quinoxalin-2-ylamino)benzoyl]amino]pyrimidin-1-yl]propanoyl]amino]butanoic acid | Ligand Info | |||||
| Structure Description | Crystal structure of human Caspase-1 with N-{3-[1-((S)-2-Hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl}-4-(quinoxalin-2-ylamino)-benzamide | PDB:6F6R | ||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [16] |
| PDB Sequence |
> Chain A
QDNPAMPTSS 127 GSEGNVKLCS137 LEEAQRIWKQ147 KSAEIYPIMD157 KSSRTRLALI167 ICNEEFDSIP 177 RRTGAEVDIT187 GMTMLLQNLG197 YSVDVKKNLT207 ASDMTTELEA217 FAHRPEHKTS 227 DSTFLVFMSH237 GIREGICGKK247 HSEQVPDILQ257 LNAIFNMLNT267 KNCPSLKDKP 277 KVIIIQACRG287 DSPGVVWFKD297 > Chain B AIKKAHIEKD 326 FIAFCSSTPD336 NVSWRHPTMG346 SVFIGRLIEH356 MQEYACSCDV366 EEIFRKVRFS 376 FEQPDGRAQM386 PTTERVTLTR396 CFYLFPGH
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ARG179[A]
2.806
SER236[A]
3.822
HIS237[A]
3.989
GLY238[A]
3.914
GLN283[A]
2.752
ALA284[A]
3.756
CYS285[A]
1.752
VAL338[B]
3.967
SER339[B]
2.827
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| Ligand Name: (3S)-3-[[(3S,6S,10aS)-6-(isoquinoline-1-carbonylamino)-5-oxo-2,3,6,7,8,9,10,10a-octahydro-1H-pyrrolo[1,2-a]azocine-3-carbonyl]amino]-4-hydroxybutanoic acid | Ligand Info | |||||
| Structure Description | Crystal structure of human Caspase-1 with (3S,6S,10aS)-N-((2S,3S)-2-hydroxy-5-oxotetrahydrofuran-3-yl)-6-(isoquinoline-1-carboxamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide (PGE-3935199) | PDB:5MTK | ||||
| Method | X-ray diffraction | Resolution | 2.53 Å | Mutation | No | [17] |
| PDB Sequence |
> Chain A
GSEGNVKLCS 137 LEEAQRIWSA150 EIYPIMDKSS160 RTRLALIICN170 EEFDSIPRRT180 GAEVDITGMT 190 MLLQNLGYSV200 DVKKNLTASD210 MTTELEAFAH220 RPEHKTSDST230 FLVFMSHGIR 240 EGICGKKHSE250 QVPDILQLNA260 IFNMLNTKNC270 PSLKDKPKVI280 IIQACRGDSP 290 GVVWFK> Chain B IKKAHIEKDF 327 IAFCSSTPDN337 VSWRHPTMGS347 VFIGRLIEHM357 QEYACSCDVE367 EIFRKVRFSF 377 EQPDGRAQMP387 TTERVTLTRC397 FYLFPGH
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Necroptosis | hsa04217 | Affiliated Target |
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| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Neutrophil extracellular trap formation | hsa04613 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| NOD-like receptor signaling pathway | hsa04621 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Cytosolic DNA-sensing pathway | hsa04623 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| C-type lectin receptor signaling pathway | hsa04625 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 22 | Degree centrality | 2.36E-03 | Betweenness centrality | 1.55E-03 |
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| Closeness centrality | 2.35E-01 | Radiality | 1.41E+01 | Clustering coefficient | 1.17E-01 |
| Neighborhood connectivity | 2.30E+01 | Topological coefficient | 6.00E-02 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 7 KEGG Pathways | + | ||||
| 1 | NOD-like receptor signaling pathway | |||||
| 2 | Cytosolic DNA-sensing pathway | |||||
| 3 | Amyotrophic lateral sclerosis (ALS) | |||||
| 4 | Salmonella infection | |||||
| 5 | Pertussis | |||||
| 6 | Legionellosis | |||||
| 7 | Influenza A | |||||
| NetPath Pathway | [+] 3 NetPath Pathways | + | ||||
| 1 | TCR Signaling Pathway | |||||
| 2 | IL2 Signaling Pathway | |||||
| 3 | TGF_beta_Receptor Signaling Pathway | |||||
| PID Pathway | [+] 4 PID Pathways | + | ||||
| 1 | IL1-mediated signaling events | |||||
| 2 | Direct p53 effectors | |||||
| 3 | IFN-gamma pathway | |||||
| 4 | Cellular roles of Anthrax toxin | |||||
| Reactome | [+] 3 Reactome Pathways | + | ||||
| 1 | NOD1/2 Signaling Pathway | |||||
| 2 | Interleukin-1 processing | |||||
| 3 | The NLRP3 inflammasome | |||||
| WikiPathways | [+] 8 WikiPathways | + | ||||
| 1 | MAPK Signaling Pathway | |||||
| 2 | Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways | |||||
| 3 | Apoptosis | |||||
| 4 | Amyotrophic lateral sclerosis (ALS) | |||||
| 5 | Parkin-Ubiquitin Proteasomal System pathway | |||||
| 6 | Interleukin-1 processing | |||||
| 7 | Apoptosis Modulation and Signaling | |||||
| 8 | NOD pathway | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydr... J Pharmacol Exp Ther. 2007 May;321(2):509-16. | |||||
| REF 2 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 3 | Pralnacasan, an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in two murine models of osteoarthritis. Osteoarthritis Cartilage. 2003 Oct;11(10):738-46. | |||||
| REF 4 | Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats. Apoptosis. 2013 Dec;18(12):1481-91. | |||||
| REF 5 | 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. (Ligand id: 6467). | |||||
| REF 6 | Caspase inhibitors: a review of recently patented compounds (2013-2015).Expert Opin Ther Pat. 2018 Jan;28(1):47-59. | |||||
| REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006085) | |||||
| REF 8 | Interleukin-1 beta converting enzyme inhibition blocks progression of type II collagen-induced arthritis in mice. Cytokine. 1996 May;8(5):377-86. | |||||
| REF 9 | IL-converting enzyme/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from familial cold autoinflammatory syndrome patients. J Immunol. 2005 Aug 15;175(4):2630-4. | |||||
| REF 10 | Succinic acid amides as P2-P3 replacements for inhibitors of interleukin-1beta converting enzyme (ICE or caspase 1). Bioorg Med Chem Lett. 2010 Sep 1;20(17):5184-90. | |||||
| REF 11 | Reduction of inflammation and pyrexia in the rat by oral administration of SDZ 224-015, an inhibitor of the interleukin-1 beta converting enzyme. Br J Pharmacol. 1995 Jun;115(4):601-6. | |||||
| REF 12 | Novel pyrazinone mono-amides as potent and reversible caspase-3 inhibitors. Bioorg Med Chem Lett. 2005 Feb 15;15(4):1173-80. | |||||
| REF 13 | Mice deficient in interleukin-1beta converting enzyme resist anorexia induced by central lipopolysaccharide. Am J Physiol. 1999 Nov;277(5 Pt 2):R1435-43. | |||||
| REF 14 | Tethering identifies fragment that yields potent inhibitors of human caspase-1. Bioorg Med Chem Lett. 2006 Feb;16(3):559-62. | |||||
| REF 15 | Different molecular events account for butyrate-induced apoptosis in two human colon cancer cell lines. J Nutr. 2002 Jul;132(7):1812-8. | |||||
| REF 16 | Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne. J Med Chem. 2018 May 10;61(9):4030-4051. | |||||
| REF 17 | Playing against the odds: scaffold hopping from 3D-fragments | |||||
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